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662

Practice Guidelines for the Treatment of Candidiasis

John H. Rex,1 Thomas J. Walsh,2 Jack D. Sobel,3

Scott G. Filler,4 Peter G. Pappas,5

William E. Dismukes,5 John E. Edwards4

From the 1Division of Infectious Diseases, Department of Internal

Medicine, Center for the Study of Emerging and Re-emerging

Pathogens, University of Texas Medical School, Houston;2

InfectiousDiseases Section, Pediatric Branch, National Cancer Institute,

Bethesda, Maryland; 3Wayne State University School of Medicine,

Detroit, Michigan; 4Harbor-UCLA Medical Center, Torrance,

California; 5Department of Medicine, Division of Infectious Diseases,

University of Alabama at Birmingham

Executive Summary

Infections due to Candida species are the most common of

the fungal infections. Candida species produce a broad range

of infections, ranging from non–life-threatening mucocutan-

eous illnesses to invasive process that may involve virtually any

organ. Such a broad range of infections requires an equallybroad range of diagnostic and therapeutic strategies. This doc-

ument summarizes current knowledge about treatment of mul-

tiple forms of candidiasis and is the guideline of the Infectious

Diseases Society of America (IDSA) for the treatment of can-

didiasis. Throughout this document, treatment recommenda-

tions are scored according to the standard scoring scheme used

in other IDSA guidelines to illustrate the strength of the un-

derlying data. The document covers 4 major topical areas.

The role of the microbiology laboratory. To a greater extent

than forother fungi, treatment of candidiasis can nowbe guided

by in vitro susceptibility testing. The guidelines review the avail-

able information supporting current testing procedures and in-

terpretive breakpoints and place these data into clinical context.

Susceptibility testing is most helpful in dealing with infection

due to non-albicans species of Candida. In this setting, especially

if the patient has been treated previously with an azole anti-

fungal agent, the possibility of microbiological resistance must

be considered.

Treatment of invasive candidiasis. In addition to acute he-

matogenous candidiasis, the guidelines review strategies for

treatment of 15 other forms of invasive candidiasis. Extensive

data from randomized trials are really available only for ther-

apy of acute hematogenous candidiasis in the nonneutropenic

adult. Choice of therapy for other forms of candidiasis is based

on case series and anecdotal reports. In general, both ampho-

Received 10 May 1999; revised 10 June 1999; electronically published 20

April 2000.

This guideline is part of a series of updated or new guidelines from the

IDSA that will appear in CID.

Reprints and correspondence: Dr. John H. Rex, Division of Infectious

Diseases, Dept. of Internal Medicine, Center for the Study of Emerging and

Re-emerging Pathogens, University of Texas Medical School, 6431 Fannin,

1728 JFB, Houston, TX 77030 ([email protected])

Clinical Infectious Diseases 2000;30:662–78

2000 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2000/3004-0008$03.00

tericin B and the azoles have a role to play in treatment. Choice

of therapy is guided by weighing the greater activity of am-

photericin B for some non-albicans species (e.g., Candida krusei )

against the lesser toxicity and ease of administration of the

azole antifungal agents. Flucytosine has activity against many

isolates of Candida but is not often used.

Treatment of mucocutaneous candidiasis. Therapy for mu-cosal infections is dominated by the azole antifungal agents.

These drugs may be used topically or systemically and have

been proven safe and efficacious. A significant problem with

mucosal disease is the propensity for a small proportion of

patients to suffer repeated relapses. In some situations, the ex-

planation for such a relapse is obvious (e.g., relapsing oro-

pharyngeal candidiasis in an individual with advanced and un-

controlled HIV infection), but in other patients the cause is

cryptic (e.g., relapsing vaginitis in a healthy woman). Rational

strategies for these situations are discussed in the guidelines

and must consider the possibility of induction of resistance over

time.

Prevention of invasive candidiasis. Prophylactic strategies

are useful if the risk of a target disease is sharply elevated in

a readily identified group of patients. Selected patient groups

undergoing therapy that produces prolonged neutropenia

(e.g., some bone-marrow transplant recipients) or who receive

a solid-organ transplant (e.g., some liver transplant recipients)

have a sufficient risk of invasive candidiasis to warrant

prophylaxis.

Introduction

Relationship between epidemiology of candidal infections and

therapy. Although Candida albicans remains the most com-mon pathogen in oropharyngeal and cutaneous candidiasis,

non-albicans species of Candida are increasingly frequent prob-

lems in both invasive candidiasis [1] and vaginal candidiasis [2].

This is particularly problematic in patients with acutely life-

threatening invasive candidal infections. Although the suscep-

tibility of Candida to the currently available antifungal agents

can be predicted if the species of the infecting isolate is known

(table 1) [1, 3–13], individual isolates do not necessarily follow

the general pattern. For example, C. albicans is usually sus-

ceptible to all major agents. However, azole resistance for this



CID 2000;30 (April) Treatment Guidelines for Candidiasis 663

Table 1. General patterns of susceptibility of Candida species.

Candida species Fluconazole Itraconazole Flucytosine Amphotericin B

C. albicans S S S S

C. tropicalis S S S S

C. parapsilosis S S S S

C. glabrata S-DD to Ra S-DD to Rb S S-Ic

C. krusei R S-DD to Rb

I-R S-Ic

C. lusitaniae S S S S to Rd

NOTE. Except for amphotericin B, interpretations are based on use of a

reference broth susceptibility testing method [3], and the underlying data were

drawn from a variety of sources [1, 4–7]. Data for amphotericin B also include

results of studies in which modifications of the reference method have been used

in enhanced detection of amphotericin B–resistant isolates [4, 8, 9]. See table 2

for the specific interpretive breakpoints used to construct this table. I, interme-

diate; R, resistant; S, susceptible; S-DD, susceptible-dose dependent (the category

S-DD is discussed in the section Susceptibility Testing and Drug Dosing, in the

Introduction).a

On the basis of a survey of recent bloodstream isolates [1], 15% of C. glabrata

isolates are resistant to fluconazole.b

In addition, 46% of C. glabrata isolates and 31% of C. krusei isolates are

resistant to itraconazole.c

On the basis of a combination of in vitro data [8, 10] and in vivo data [11,12], it appears that a significant proportion of the isolates of C. glabrata and C.

krusei have reduced susceptibility to amphotericin B.d

Although frank amphotericin B resistance is not seen in all isolates, it is well

described for isolates of this species [13, 14].

species is now well described among HIV-infected individuals

with relapsing oropharyngeal candidiasis and is also reported

sporadically in critically ill adults with invasive candidiasis [14].

For this reason, susceptibility testing for azole resistance is in-

creasingly important in the management of candidiasis in pa-

tients. On the other hand, most Candida isolates appear to

remain susceptible to amphotericin B, although recent data

suggest that isolates of Candida glabrata and C. krusei mayrequire maximal doses of amphotericin B (see below).

Susceptibility testing and drug dosing. Intensive efforts to

develop standardized, reproducible, and clinically relevant sus-

ceptibility testing methods for the fungi have resulted in the

development of the NCCLS M27-A methodology for suscep-

tibility testing of yeasts [15]. Data-driven interpretive break-

points using this method are available for testing the suscep-

tibility of Candida species to fluconazole, itraconazole, and

flucytosine [15–17]. Several features of these breakpoints are

important. First, these interpretive breakpoints should not be

used with other methods without extensive testing. Although

the M27-A methodology is not the only possible way to de-

termine a minimum inhibitory concentration (MIC), use of theM27-A interpretive breakpoints with other methods should be

approached with caution—even small methodological varia-

tions may produce results that are not correctly interpreted by

means of these breakpoints. Second, these interpretive break-

points place a strong emphasis on interpretation in the context

of the delivered dose of the azole antifungal agent. The novel

category S-DD (susceptible-dose/delivery dependent) indicates

that maximization of dosage and bioavailability are critical to

successful therapy. In the case of fluconazole, both human and

animal data suggest that S-DD isolates may be treated suc-

cessfully with 12 mg/kg/d [16, 18]. Although trials to date have

not used this method, administration of twice the usual daily

dose of fluconazole as a loading dose is a pharmacologically

rational way to achieve more rapidly the higher blood levels

of steady state. In the case of itraconazole, oral absorption issomewhat unpredictable, and achievement of blood levels of

0.5 mg/mL (as determined by high-performance liquid chro-

matography) appears important to successful therapy. Finally,

these breakpoints have been developed on the basis of data

from 2 groups of infected patients: patients with oropharyngeal

and esophageal candidiasis (fluconazole and itraconazole [16])

and patients with invasive candidiasis (mostly nonneutropenic

patients with candidemia; fluconazole only [16, 17]). Although

these limitations are similar to those of interpretive breakpoints

for antibacterial agents, and although extrapolation of these

results to other settings appears rational on the basis of data

from in vivo therapy models, it is still prudent to consider the

limitations of the data when making use of the breakpoints.Pharmacology, safety, published reports, and drug interactions

must be considered along with susceptibility during selection

of a therapy. For example, most isolates of Candida are sus-

ceptible to itraconazole, but this agent until recently lacked a

parenteral preparation and has been studied only as a treatment

for mucosal infections.

Reliable and convincing interpretive breakpoints are not yet

available for amphotericin B. The NCCLS M27-A methodol-

ogy does not reliably identify amphotericin B–resistant isolates

[3]. Variations of the M27-A method using different media [3],

agar-based MIC methods [8, 19, 20], and measurements of min-

imum fungicidal concentrations [7] appear to enhance detection

of resistant isolates. Although these methods are as yet insuf-

ficiently standardized to permit routine use, several generali-

zations are becoming apparent. First, amphotericin B resistance

appears uncommon among isolates of C. albicans, Candida tro-

picalis, and Candida parapsilosis. Second, isolates of Candida

lusitaniae most often demonstrate readily detectable and clin-

ically apparent amphotericin B resistance. However, the exact

frequency of this event is uncertain, and not all isolates are

resistant [7, 12]. Third, a growing body of data suggests that

a nontrivial proportion of the isolates of C. glabrata and C.

krusei may be resistant to amphotericin B [7, 9–11]. Impor-

tantly, delivery of additional amphotericin B by use of a lipid-

based preparation of amphotericin B may not always be ade-quate to overcome this resistance [11]. Also, because of in vitro

effects of the lipid, tests for susceptibility to amphotericin B

should always use amphotericin B itself rather than a lipid-

associated form of the drug [21]. Unfortunately, the true fre-

quency and clinical relevance of these observations is uncertain.

Most rational current therapy for infections due to these species

(C. lusitaniae, C. glabrata, and C. krusei ) thus revolves around

(a) awareness of the possibility of true microbiological resis-

tance among the species and (b) judicious and cautious use of

susceptibility testing. When amphotericin B deoxycholate is



664 Rex et al. CID 2000;30 (April)

used to treat infections due to C. glabrata or C. krusei, doses

approaching or exceeding 1 mg/kg/d may be needed, especially

in profoundly immunocompromised hosts.

Lipid-based amphotericin B preparations. Three lipid for-

mulations of amphotericin B have been developed and ap-proved for use in humans: amphotericin B lipid complex

(ABLC, Abelcet; Liposome, Princeton, NJ), amphotericin B

colloidal dispersion (ABCD, Amphotec; Sequus Pharmaceu-

ticals, Menlo Park, CA), and liposomal amphotericin B (Am-

Bisome; Vestar, San Dimas, CA). Only ABLC and liposomal

amphotericin B have been approved for use in proven candi-

diasis. These approvals are for second-line therapy of patients

who are intolerant of or refractory to therapy with conventional

amphotericin B (defined in one study using ABLC [22] as failure

of 500 mg amphotericin B, initial renal insufficiency (creat-

inine 2.5 mg/dL or creatinine clearance !25 mL/min), a sig-

nificant rise in creatinine (to 2.5 mg/dL for adults or 1.5 mg/

dL for children), or severe acute administration-relatedtoxicity). Patients with invasive candidiasis also have been

treated successfully with ABCD [23, 24]. Both in vivo and clin-

ical studies indicate that these compounds are less toxic but as

effective as amphotericin B when used in appropriate dosages

[25, 26]. Nevertheless, their higher cost and the paucity of ran-

domized trials in proven invasive candidiasis limit their front-

line use in these infections. These agents dramatically alter the

pharmacology of amphotericin B, and the full implications of

these changes are not yet known [27, 28].

Thus, with regard to Candida infections, amphotericin B

deoxycholate remains the standard agent. As discussed in the

overview for these guidelines [29], a lipid-associated ampho-

tericin B would be appropriate in patients who are refractory

to this therapy, intolerant of this therapy, or at high risk of

being intolerant of this approach (e.g., high risk for nephro-

toxicity due to pre-existing renal dysfunction or continued con-

comitant use of another nephrotoxic agent, such as cis-plati-

num, an aminoglycoside, or cyclosporine). These agents are

licensed at 5 mg/kg/d (ABLC), 3–6 mg/kg/d (ABCD), and 3–5

mg/kg/d (liposomal amphotericin B). The optimal dose of these

compounds for serious Candida infections is unclear, and the

agents appear generally equipotent. Doses of 3–5 mg/kg would

appear suitable for treatment of most serious candidal

infections.

Appropriate dosages for pediatric patients. The topic of an-tifungal pharmacology in children and infants has been re-

viewed in detail [30]. Data on dosing of the antifungal agents

in pediatric patients are limited. Amphotericin B appears to

have similar kinetics in neonates and adults [31]. A phase 1–2

study of ABLC at 2–5 mg/kg/d in the treatment of hepato-

splenic candidiasis in children found that the area under the

curve and the maximal concentration of drug were similar to

those of adults and that steady state appeared to be achieved

by ∼7 days [32]. A phase 1–2 study of liposomal amphotericin

B is currently in progress. Because clearance of flucytosine is

directly proportional to glomerular filtration rate, very-low–

birth weight infants may accumulate high plasma concentra-

tions because of immature renal function [33]. The pharma-

cokinetics of fluconazole varies with age [34–37]. Because of its

more rapid clearance in children (plasma half-life,∼

14 h) [34],fluconazole should be administered at 6 mg/kg q12h for treat-

ment of life-threatening infections. In comparison with the vol-

ume of distribution seen in adults (0.7 L/kg), neonates may

have a 2–3 fold higher volume of distribution that falls to !1

L/kg by 3 months of age. In comparison with the half-life of

fluconazole in adults (30 h), neonates have a prolonged half-

life of 55–90 h [38]. Despite this prolonged half-life, once-daily

dosing seems prudent in low– and very-low–birth weight infants

who are being treated for disseminated candidiasis. A dosage

of 5 mg/kg/d has been used safely and successfully in this pop-

ulation [39]. Itraconazole cyclodextrin oral solution given at 5

mg/kg/d to infants and children was found to provide poten-

tially therapeutic concentrations in plasma [40]. The levels were,however, substantially lower than those attained in adult pa-

tients with cancer, particularly in children aged 6 months to 2

years. A recent study of 2.5 mg/kg/d and 5 mg/kg/d of cyclo-

dextrin itraconazole in HIV-infected children did document ef-

ficacy in the treatment of oropharyngeal candidiasis in pediatric

patients [41]. The newly licensed iv formulation of itraconazole

has not been studied in the pediatric setting.

These practice guidelines provide recommendations for treat-

ment of various forms of candidiasis. For each form, we specify

objectives; treatment options; outcomes of treatment; evidence;

values; benefits, harms, and costs; and key recommendations.

Candidemia and Acute Hematogenously Disseminated

Candidiasis

Objective. To resolve signs and symptoms of associated

sepsis, to sterilize the bloodstream and any clinically evident

sites of hematogenous dissemination, and to treat occult sites

of hematogenous dissemination.

Treatment options. Intravenous amphotericin B, iv or oral

fluconazole. Flucytosine could be considered in combination

with one of these agents for more-severe infections (CIII; see

article by Sobel [42] for definitions of categories reflecting the

strength of each recommendation for or against its use and

grades relecting the quality of evidence on which recommen-dations are based). Removal of existing intravascular catheters

is desirable if feasible, especially in nonneutropenic patients

(BII).

(Note added in proof: An iv preparation of itraconazole in

hydroxy-propyl-b-cyclodextrin has recently been licensed. This

formulation is given at 200 mg q12h for 4 doses (2 d) followed

by 200 mg/d and was licensed on the basis of evidence that this

dosing regimen achieves adequate blood levels more rapidly

and with less patient-to-patient variability than the oral prep-

arations of the drug [43–45]. Formal studies of iv itraconazole




Table 2. Interpretive breakpoints for isolates of Candida.

Drug

Minimum inhibitory concentration, mg/mL

S S-DD or I R

Fluconazole 8 S-DD, 16–32 132

Itraconazole 0.125 S-DD, 0.25–0.5 10.5

Flucytosine 4 I, 8–16 116

NOTE. Shown are the breakpoints proposed for use with the reference broth

susceptibility testing method [3] for Candida [16]. Isolates of Candida krusei are

assumed to be intrinsically resistant to fluconazole, and breakpoints for these

isolates do not apply. I, intermediate; R, resistant; S, susceptible; S-DD, suscep-

tible-dose dependent (the category S-DD is discussed in the section Susceptibility

Testing and Drug Dosing, in the Introduction).

as therapy for invasive candidiasis are in progress but as yet

are incomplete. The discussion of therapeutic options for this

and all other forms of candidiasis will thus generallynot address

iv itraconazole.)

Outcomes. Clearance of bloodstream and other clinicallyevident sites of infection, symptomatic improvement, absence

of retinal findings of Candida endophthalmitis, adequate fol-

low-up to ensure that late-appearing symptoms of focal he-

matogenous spread are not overlooked.

Evidence. Candida bloodstream infections are frequently

associated with clinical evidence of the sepsis syndrome and

high associated attributable mortality [46]. In addition, he-

matogenous seeding may compromise the function of one or

more organs. Two recent large randomized studies [47, 48] and

2 recent large observational studies [49, 50] have demonstrated

that fluconazole at 400 mg/d and amphotericin B at 0.5–0.6

mg/kg/d are similarly effective as therapy. The randomized stud-

ies are limited to nonneutropenic patients, whereas the obser-vational studies provide data suggesting that fluconazole and

amphotericin B are similarly effective in neutropenic patients.

ABLC and liposomal amphotericin B are indicated for patients

intolerant of or refractory to conventional antifungal therapy

(defined in one study using ABLC [22] as failure of 500 mg

amphotericin B, initial renal insufficiency [creatinine 2.5 mg/

dL or creatinine clearance !25 mL/min], a significant increase

in creatinine [to 2.5 mg/dL for adults or 1.5 mg/dL for children],

or severe acute administration-related toxicity). Open-label

therapy of candidemia with ABCD at 2–6 mg/kg/d has been

successful [24]. In a randomized trial, ABLC at 5 mg/kg/d was

found to be equivalent to 0.6–1.0 mg/kg/d amphotericin B as

therapy for nosocomial candidiasis (mostly candidemia) [51].

Candidemia due to C. parapsilosis has increased in frequency

among pediatric populations and appears to be associated with

a lower mortality rate than other species of Candida [52–54]

Values. Without adequate therapy, endophthalmitis, en-

docarditis, and other severe disseminated forms of candidiasis

may complicate candidemia. Given the potential severity of the

clinical syndrome, it is important that the initial empirical

choice be adequate to address the most likely species and their

associated susceptibility to the various agents

Benefits, harms, and costs. Effective therapy is potentially

lifesaving. Amphotericin B–induced nephrotoxicity can com-

plicate management of critically ill patients.Key recommendations. If feasible, initial nonmedical man-

agement should include removal of all existing central venous

catheters (BII). The evidence for this recommendation is strong-

est in the nonneutropenic patient population [50, 55]. In neu-

tropenic patients, the role of the gut as a sourcefor disseminated

candidiasis is evident from autopsy studies, but in an individual

patient it is difficult to determine the relative contribution of

gut versus catheter as the primary source of fungemia [49, 50].

An exception is made for fungemia due to C. parapsilosis, which

is very frequently associated with catheters (AII) [49].

Choice of medical therapy depends on both the clinical status

of the patient and the physician’s knowledge of the species and/

or antifungal susceptibility of the infecting isolate. In stable

patients who have not recently received azole therapy, most

experts would initiate therapy with fluconazole at

6 mg/kg/d(i.e., 400 mg/d in a 70-kg patient) [56]. In the clinically unstable

patient infected with an isolate of unknown species, fluconazole

has been used successfully, but amphotericin B at 0.7 mg/kg/

d is preferred by some authorities [56] because of its broader

spectrum (table 1). Neonates with disseminated candidiasis are

usually treated with amphotericin B because of its low toxicity

and because of the lack of experience with other agents in this

population. Antifungal susceptibility can be broadly predicted

once the isolate has been identified to the species level (see the

section on Susceptibility and Drug Dosing in the Introduction,

above). C. albicans, C. tropicalis, and C. parapsilosis may be

treated with either amphotericin B at 0.6 mg/kg/d or fluconazole

at 6 mg/kg/d (AI). Because C. glabrata often has reduced sus-ceptibility to both azoles and amphotericin B, opinions on best

empirical therapy are divided. Although some patients have

been treated successfully with fluconazole at 6 mg/kg/d, most

authorities recommend amphotericin B at 0.7 mg/kg/d as in-

itial therapy (BIII). Fluconazole at 12 mg/kg/d (800 mg/d in a

70-kg patient) may also be suitable, particularly in less–critically

ill patients (BIII). If the infecting isolate is known or likely to

be C. krusei, available data suggest that amphotericin B at 1.0

mg/kg/d is preferred (BIII). Many but not all isolates of C.

lusitaniae are resistant to amphotericin B; thus, fluconazole at

6 mg/kg/d is the preferred therapy for this species (BIII). Issues

related to selection and dosage of the lipid amphotericin prep-

arations are discussed in the section Lipid-Based AmphotericinB Preparations in the Introduction, above. As discussed in the

section Susceptibility Testing and Drug Dosing (in the Intro-

duction, above), susceptibility testing of the infecting isolate is

a useful adjunct to species identification during selection of a

therapeutic approach, since it can be used to identify isolates

that are unlikely to respond to fluconazole (AII) or ampho-

tericin B (BII) table 2) [16]. For candidemia, therapy should

be continued for 2 weeks after the last positive blood culture

and resolution of signs and symptoms of infection (AIII). Am-

photericin B may be switched to fluconazole (iv or po) for




completion of therapy (BIII). The duration of therapy for pa-

tients with evidence of visceral spread is discussed elsewhere.

As discussed elsewhere [57], patients who are neutropenic at

the time of developing candidemia should receive a recombi-

nant cytokine that accelerates recovery from neutropenia (G-CSF or GM-CSF).

Empirical Therapy for Suspected Disseminated Candidiasis

in Febrile Nonneutropenic Patients

Objective. To treat early occult Candida infection.

Treatment options. Intravenous amphotericin B or iv or

oral fluconazole.

Outcomes. Reduction in fever and prevention of devel-

opment of overt candidal bloodstream infection and the com-

plications of hematogenously disseminated candidiasis.

Evidence. Although Candida is now the fourth most com-

mon bloodstream isolate and is the most common invasive

fungal infection in critically ill nonneutropenic patients, accu-

rate early diagnostic tools for invasive candidiasis are lacking.

Colonization by Candida of multiple nonsterile sites, prolonged

use of antibacterial antibiotics, central venous catheters, hy-

peralimentation, surgery (especially surgery that transects the

gut wall), and prolonged ICU stay have all been linked to

increased risk of invasive candidiasis [58–60]. Although empir-

ical therapy is intuitively attractive, compelling data defining

appropriate subsets of patients for such therapy are lacking.

Values. Prevention of clinically evident invasive candidiasis

could potentially reduce morbidity and mortality.

Benefits, harms, and costs. Given the ill-defined nature of

this syndrome, preference is often given to therapies with lesser

toxicity. Widespread use of inappropriate antifungal therapy

may have deleterious epidemiological consequences, including

selection of resistant organisms.

Key recommendations. Appropriate use of antifungal ther-

apy in this setting has not been defined. If therapy is given, its

use should be limited to patients with (a) Candida colonization

(preferably at multiple sites [58]), (b) multiple other risk factors,

and (c) absence of any other uncorrected causes of fever (CIII).

Empirical Antifungal Therapy for Neutropenic Patients

with Prolonged Fever Despite Antibacterial Therapy

Objective. To treat early occult fungal infection.

Treatment options. Empirical therapy should address both

yeast and mold infections. Until recently, amphotericin B was

the only sufficiently broad-spectrum agent available in a reliable

parenteral form. Itraconazole has an adequate antifungal spec-

trum of activity and may represent a suitable alternative ther-

apy [61]. However, extensive data with it in this setting are not

yet available, and its proper role for empirical antifungal ther-

apy remains to be determined. If used, initiation of therapy

with the iv formulation is appropriate, as the bioavailability of

the current oral formulations of itraconazole (including the

cyclodextrin solution) is unpredictable [62, 63]. Fluconazole is

often inappropriate because of both prior fluconazole therapy

and its limited spectrum.

Outcomes. Resolution of fever and prevention of devel-opment of clinically overt infection

Evidence. Randomized prospective clinical trialshave dem-

onstrated that neutropenic patients with persistent fever despite

broad-spectrum antimicrobial therapy have an ∼20% risk of

developing an overt invasive fungal infection [64, 65]. Empirical

antifungal therapy reduces the frequency of development of

clinically overt invasive fungal infection in this high-risk pop-

ulation [64–66].

Values. Early antifungal therapy is more likely to succeed

in neutropenic patients. Advanced infection is associated with

high morbidity and mortality.

Benefits, harms, and costs. Early treatment of fungal in-

fections should reduce fungal infection–associated morbidity.Key recommendations. Therapy is appropriate in neutro-

penic patients who have persistent unexplained fever despite

4–6 days of appropriate antibacterial therapy. Once begun, ther-

apy is continued until resolution of neutropenia. Amphotericin

B at 0.5–0.7 mg/kg/d has traditionally been the preferred agent

(AII). When compared with amphotericin B at 0.6 mg/kg/d

(median dose), liposomal amphotericin B (AmBisome) at 3 mg/

kg/d (median dose) has been shown to have similar overall

clinical efficacy in the primary analysis. In secondary analyses,

liposomal amphotericin B showed superior safety and tolerance

and a decreased rate of documented breakthrough fungal in-

fections, particularly in bone-marrow transplant recipients (AI)

[67].

Chronic Disseminated Candidiasis (Hepatosplenic

Candidiasis)

Objective. To eradicate foci of chronic disseminated

candidiasis.


fluconazole. Flucytosine could be considered in combination

with 1 of these agents for more-refractory infections.

Outcomes. Resolution of clinical signs and symptoms

of infection, resolution of radiographic findings of visceral

involvementEvidence. Open-label and observational studies have eval-

uated the utility of amphotericin B [68, 69], lipid-associated

amphotericin B [32], and fluconazole [70, 71].

Values. This syndrome is not acutely life-threatening but

does require prolonged therapy to produce a cure. Thus, im-

portance is placed on use of a convenient and nontoxic long-

term regimen.

Benefits, harms, and costs. Amphotericin B, although ef-

ficacious, requires iv therapy. Fluconazole can be given orally.

Key recommendations. Fluconazole at 6 mg/kg/d is gen-




erally preferred in stable patients (BIII). Amphotericin B at

0.6–0.7 mg/kg/d may be used in acutely ill patients or patients

with refractory disease. Some but not all experts recommend

an initial 1- to 2-week course of amphotericin B for all patients,

followed by a prolonged course of fluconazole [56]. Therapyshould be continued until calcification or resolution of lesions,

particularly in patients receiving continued chemotherapy or

immunosuppression. Premature discontinuation of antifungal

therapy may lead to recurrent infection. Patients with chronic

disseminated candidiasis may continue to receive chemother-

apy, including ablative therapy for bone marrow/stem cell trans-

plantation. Treatment of chronic disseminated candidiasis in

these cases continues throughout chemotherapy [69].

Disseminated Cutaneous Neonatal Candidiasis

Objective. To treat infants with disseminated cutaneous

neonatal candidiasis (also known as congenital candidiasis)

who are at high risk for developing acute disseminated

candidiasis.

Treatment options. In healthy, normal birth weight, term

infants, therapy of the primary cutaneous disease with topical

agents is generally appropriate. In patients at risk for acute

bloodstream or visceral dissemination, therapies used for acute

disseminated candidiasis are appropriate.

Outcomes. The neonatal candidiasis syndrome is a unique

syndrome in which widespread dermatitis due to Candida is

seen in neonates. This syndrome is thought to be secondary to

contamination of the amniotic fluid, and, in healthy, term in-fants, this process is usually limited to the skin and resolves

with topical therapy [72]. However, in premature or low–birth

weight neonates or infants with prolonged rupture of mem-

branes, the cutaneous process may become invasive and thus

produce acute disseminated candidiasis [73].

Evidence. Essentially all data are derived from small case

series and individual reports. Most reports have been limited

to use of amphotericin B.

Values. If not anticipated and treated, development of

acute disseminated candidiasis can be lethal.

Benefits, harms, and costs. Amphotericin B is well tolerated

in neonates. Fluconazole has not been as well studied. In par-

ticular, the pharmacology of fluconazole varies with neonatalage, making rational dosing somewhat difficult [31, 35, 36].

Key recommendations Premature neonates, low–birth weight

neonates, or infants with prolonged rupture of membranes who

demonstrate the clinical findings of disseminated neonatal cu-

taneous candidiasis should be considered for systemic therapy.

Amphotericin B at 0.5–1 mg/kg/d for a total dose of 10–25 mg/

kg is generally used (BIII). Fluconazole may be used as a sec-

ond-line agent (BIII; dosing issues for the azole antifungals for

children are discussed in the section Appropriate Dosages for

Pediatric Patients, in the Introduction, above).

Urinary Candidiasis

Objective. To eradicate signs and symptoms associated

with parenchymal infection of the urinary collecting system. In

selected patients, such therapy might reduce the risk of as-

cending or disseminated infection.

Treatment options. Fluconazole (oral or iv), amphotericin

B (iv), or flucytosine (oral). Amphotericin B bladder irrigation

fails to treat disease above the level of the bladder.

Outcomes. Clearance of the urine.

Evidence. Urinary candidiasis includes an ill-defined group

of syndromes [74]. The most common risk factors for candi-

duria include urinary tract instrumentation, recent antibiotic

therapy, and advanced age [75]. Candida is now the most fre-

quently isolated organism from the urine of patients in surgical

intensive care units. In most patients, isolation of Candida rep-

resents only colonization and is a benign event. In candiduric

individuals, Foley catheter change alone rarely results in elim-

ination of candiduria (!20%); however, discontinuation of the

catheter alone may result in eradication of candiduria in almost

40% of patients [76] (BIII). A recently completed placebo-

controlled trial found that fluconazole at 200 mg/d for 14 d

hastened the time to a negative urine culture, but that 2 weeks

after the end of therapy the frequency of a negative urine culture

was the same in both treatment groups (∼60% for catheterized

patients and ∼73% for noncatheterized patients) [76]. In other

patients, candiduria may be the source of subsequent dissem-

ination (e.g., a patient with obstructive uropathy) [77] or a

marker of acute hematogenous dissemination [74]. These con-

cerns are especially applicable to neutropenic patients, patients

without current or recent instrumentation of the urinary tract,and low–birth weight infants. Data on the outcome of therapy

are limited by the heterogeneity of the underlying diseases and

the lack of clear definitions.

Values. Therapy of asymptomatic candiduria in the non-

neutropenic catheterized patient has never been shown to be

of value. Candiduria in neutropenic patients, critically-ill pa-

tients in intensive care units, low–birth weight infants, and

transplant recipients may be a clue to disseminated candidiasis.

Benefits, harms, and costs. Therapy of appropriately se-

lected patients may reduce the risk of ascending and/or he-

matogenously disseminated disease. Therapy of persistently

febrile patients who have candiduria but who lack evidence for

infections at other sites may treat occult disseminated candi-diasis. Inappropriate therapy may select for resistantorganisms.

Key recommendations. Asymptomatic candiduria rarely re-

quires therapy (DIII). Candiduria may, however, be the only

microbiological documentation of disseminated candidiasis.

Candiduria should be treated in symptomatic patients, neutro-

penic patients, low–birth weight infants, patients with renal

allografts, and patients who will undergo urologic manipula-

tions (BIII). However, as with any other complicated urinary

tract infection, short courses of therapy are not recommended

and therapy for 7–14 days is more likely to be successful. Re-




moval of urinary tract instruments, including stents and Foley

catheters, is often helpful. If complete removal is not possible,

placement of new materials may be beneficial. Therapy with

fluconazole at 200 mg/d for 7–14 days has been used, as have

courses of amphotericin B at widely ranging doses (0.3–1.0 mg/kg/d for 1–7 days) [78] (BII). In the absence of renal insuffi-

ciency, oral flucytosine at 25 mg/kg/q.i.d. may be valuable in

eradicating candiduria, especially in patients with urologic in-

fection due to non-albicans Candida species (CIII). However,

emergence of resistance to flucytosine may occur rapidly when

this compound is used as a single agent [79]. Bladder irrigation

or wash with amphotericin B (50-200 mg/mL) may transiently

clear funguria [80] but is rarely indicated (CIII) except as a

diagnostic localizing tool [81]. Even with apparently successful

local or systemic antifungal therapy, relapse is frequent and the

likelihood of relapse is increased by continued use of a urinary

catheter. Persistent candiduriain immunocompromised patients

warrants ultrasound or CT scan of the kidney (CIII).

Candidal Pneumonia

Objective. To eradicate infection and prevent loss of pul-

monary reserve.

Treatment options. Intravenous amphotericin B or flucon-

azole.

Outcomes. Clearance of local sites of infection along with

any associated sites of systemic infection.

Evidence. Observational reports and case series have

shown that proven Candida pneumonia is associated with high

mortality in patients with malignancies [82]. No convincingdata for any particular form of therapy exist.

Values. Candida pneumonia appears to exist in 2 forms.

First, after aspiration of Candida-laden oropharyngeal mate-

rial, primary pneumonia due to Candida will rarely develop

[82–84]. Second, and more common, hematogenously dissem-

inated candidiasis produces pulmonary lesions along with in-

volvement of multiple other organs. Although often entertained

as a diagnostic possibility in immunocompromised patients,

firm diagnosis of these entities is elusive and requires histo-

pathological confirmation. Finally, benign colonization of the

airway with Candida and/or contamination of the respiratory

secretions with oropharyngeal material is much more common

than either of the 2 forms of true Candida pneumonia. Thus,diagnoses of Candida pneumonia that are based solely on mi-

crobiological data will often be incorrect [85] (BIII). The di-

agnostic difficulty is further confounded by the frequent pres-

ence of Candida infection at other sites in these patients.

Benefits, harms, and costs. Injudicious use of antifungal

therapy in patients with tracheobronchial colonization or oro-

pharyngeal contamination of respiratory secretions may lead

to selection of resistant organisms. Definitive diagnosis of Can-

dida pneumonia requires histopathological confirmation.

Key recommendations. Reported therapy of patients with

primary Candida pneumonia has generally used amphotericin

B (BIII). In cases of secondary pneumonia related to hema-

togenously disseminated infection, therapy directed at dissem-

inated candidiasis rather than Candida pneumonia in particular

is indicated (see the section Candidemia and Acute Hemato-genously Disseminated Candidiasis, above).

Laryngeal Candidiasis

Objective. To treat symptoms and signs of laryngeal in-

fection and to prevent airway obstruction.

Treatment options. Intravenous amphotericin B, oral or iv

fluconazole.

Outcomes. Early clinical detection and documentation,

preferably by otolaryngologist-directed fiberoptic laryngoscopy

or indirect laryngoscopy, demonstrates localization of lesions,

allows assessment of airway patency, permits acquisition of

cultures, and enables rapid initiation of antifungal therapy. Im-

pending airway obstruction is managed by endotracheal intu-

bation. Successful medical therapy resolves laryngeal stridor,

prevents airway obstruction, and reduces the risk of aspiration

of inflammatory debris–infected Candida.

Evidence. The available data are based on small series and

individual case reports [86–88]. Most data on therapy have been

limited to amphotericin B.

Values. If not diagnosed and treated promptly, airway ob-

struction and potentially respiratory arrest may ensue.

Benefits, harms, and costs. Given the severe morbidity and

potential mortality, rapid clinical and otolaryngologic diagnosis

and prompt initiation of therapy are important and outweigh

any adverse effects of antifungal therapy.

Key recommendations. The majority of the experience has

been with amphotericin B at 0.7–1.0 mg/kg/day (BIII). Flu-

conazole may be appropriate for treatment of infection due to

susceptible isolates once symptoms and signs are improving.

There is a paucity of experience with fluconazole as primary

therapy.

Candidal Osteomyelitis (Including Mediastinitis)

and Arthritis

Objective. To relieve symptoms and eradicate infection.

Treatment options. Following open or arthroscopic debri-dement or drainage, both iv amphotericin B and oral or iv

fluconazole have been used.

Outcomes. Eradication of infection and symptoms, return

of joint function

Evidence. Multiple observational studies have been re-

ported, most of which have employed iv amphotericin B as the

primary therapy, sometimes followed by a course of an azole

antifungal agent. Only a small number of reports have de-

scribed initial therapy with an azole.

Values. Untreated disease leads to crippling disability.




Benefits, harms, and costs. The high morbidity of untreated

disease makes aggressive surgical and medical therapy appro-

priate. Surgical debridement, biopsy, and drainage also serve

to provide more-definitive histopathological and microbiolog-

ical documentation before initiation of the prolonged therapyrequired for this class of infection.

Key recommendations. Osteomyelitis is best treated initially

with surgical debridement of the affected area. Courses of am-

photericin B (0.5–1 mg/kg/d for 6–10 weeks) have been suc-

cessfully employed [89, 90]. Fluconazole has been used suc-

cessfully as initial therapy of susceptible isolates in 3 reports

in which doses of 6 mg/kg/d for 6–12 months were effective

[91–93]. Taken together, these data suggest that an initial course

of amphotericin B for 2–3 weeks followed by fluconazole for

a total duration of therapy of 6–12 months would be rational.

(BIII)

Definitive information on therapy of native joint arthritis is

limited. Adequate and/or repeated drainage is often critical tosuccessful therapy [94]. In particular, management of Candida

arthritis of the hip requires open drainage. Case reports have

documented cures with iv amphotericin B and fluconazole when

used in conjunction with adequate drainage. As parenteral ad-

ministration of these agents produces substantial synovial fluid

levels, the utility of intra-articular therapy is unclear and its

use is discouraged. Prolonged courses of therapy similar to

those used for osteomyelitis appear to be required (CIII).

Involvement of a prosthetic joint with Candida arthritis re-

quires resection arthroplasty [95]. Subsequent medical therapy

mirrors that for native joint disease, and a new prosthesis may

be inserted after successful clearance of the local infection as

defined by lack of return of symptoms after cessation of therapy(CIII).

On the basis of a small number of cases, Candida medias-

tinitis may be treated with surgical debridement followed by

either amphotericin B or fluconazole [96] (CIII). Irrigation of

the mediastinal space with amphotericin B is not recommended,

because it may cause chemical mediastinitis. Prolonged courses

of therapy, similar to those needed for osteomyelitis, appear

appropriate (CIII).

Candidal Infections of the Gallbladder, Pancreas, and

Peritoneum

Objective. To eradicate Candida infection and prevent re-

currence of infection.


fluconazole.

Outcomes. Clearance of infection as judged by resolution

of local signs and symptoms along with sterilization of cultures.

Evidence. Therapy of Candida infection of the pancreas

and biliary tree has been described in case reports and small

series. Successful therapy with either amphotericin B or flu-

conazole has been described.

Values. There are 2 major syndromes of peritoneal can-

didiasis. In disease related to peritoneal dialysis catheters, cath-

eter removal is often required for successful therapy [97–100].

Both amphotericin B and fluconazole have been used success-

fully [98–100].Candida peritonitis may also develop in association with sur-

gical or traumatic injury to the gut wall. In this setting, Candida

is usually part of a polymicrobial infection, and case series

suggest that therapy directed toward Candida is indicated, par-

ticularly when Candida is isolated as part of a complex infection

or in an immunocompromised patient (as opposed to isolation

in association with promptly repaired acute traumatic injury)

[101–103]. A recent small but placebo-controlled trial demon-

strated that fluconazole at 400 mg/d reduced the likelihood of

developing symptomatic Candida peritonitis in surgical patients

with recurrent gastrointestinal perforations or anastomotic

leakage [104].

Benefits, harms, and costs. Routine treatment of Candidaisolated after prompt and definitive repair of an acutely per-

forated viscus in otherwise healthy patients without signs of

sepsis is probably not needed and could lead to selection of

resistant organisms.

Key recommendations. Disease of the biliary tree should

be treated by mechanical restoration of functional drainage

combined with therapy with either amphotericin B or flucon-

azole (CIII). Both agents achieve therapeutic biliary concen-

trations, and local instillation is not needed [105]. Catheter-

associated peritonitis is treated with catheter removal and

systemic therapy with amphotericin B or fluconazole (BIII).

Intraperitoneal amphotericin B has been associated with pain-

ful chemical peritonitis and should in general be avoided. Can-dida peritonitis related to intra-abdominal leakage of fecal ma-

terial is treated with surgical repair, drainage, and therapy with

either amphotericin B or fluconazole (CIII). The required du-

ration of therapy for all forms of Candida peritonitis is not well

defined and should be guided by the patient’s response. In

general, 2–3 weeks of therapy seems to be required. Surgical

patients with recurrent gastrointestinal perforation are at in-

creased risk for Candida peritonitis and may benefit from pro-

phylactic antifungal therapy (BI).

Candidal Endocarditis, Pericarditis, and Suppurative

Phlebitis

Objective. To eradicate Candida infection and prevent re-

currence of infection.


fluconazole. Oral flucytosine may be added to amphotericin B.

Outcomes. Clearance of infection as judged by sterilization

of the bloodstream and preservation of cardiac function.

Evidence. All data are derived from individual case reports

and case series.

Values. Combined medical and surgical therapy is key for




all of these syndromes. Removal of infected valves, resection

of infected peripheral veins, and debridement of infected per-

icardial tissue are almost always required for successful therapy

[106, 107]. Suppurative phlebitis of the central veins has re-

sponded to prolonged medical therapy with amphotericin B[108–110]. Suppurative peripheral thrombophlebitis responds

to surgical resection of the infected vein and antifungal therapy

with amphotericin B or fluconazole [111]. The utility of anti-

coagulation as part of such purely medical therapy is uncertain.

Benefits, harms, and costs. These infections are associated

with high morbidity and mortality [112], thus justifying ag-

gressive medical and surgical therapy.

Key recommendations. Both native-valve and prosthetic-

valve infection should be managed with surgical replacement

of the infected valve. Medical therapy with amphotericin B with

or without flucytosine at maximal tolerated doses has most

often been used (BIII). Primary therapy with fluconazole has

been successfully used on occasion, but fluconazole is moreoften employed as part of a long-term suppressive regimen.

Total duration of therapy should be 6 weeks after surgery,

but possibly much longer (CIII). Candida endocarditis has a

propensity for relapse and requires careful follow-up for 1

year [113]. If valve replacement is not possible, life-long sup-

pressive therapy with fluconazole may be used (CIII) [114, 115].

Candida. Pericarditis requires surgical debridement and/or

resection, depending on the extent of the disease [116]. Cardiac

tamponade is possible and may require an emergency procedure

to relieve hemodynamic compromise. Prolonged therapy with

amphotericin B [107] or fluconazole should then be used (CIII).

Suppurative Candida thrombophlebitis of a peripheral vein

is best managed with surgical resection of the involved veinsegment, followed by antifungal therapy for 2 weeks (BIII).

Following vein resection, the general approach to this disease

is similar to that for other forms of acute hematogenous dis-

semination and the possibility of other sites of disease spread

should always be entertained.

Candidal Meningitis

Objective. To achieve rapid clearance of the infection and

return of normal neurological function.

Treatment options. Intravenous amphotericin B or flucon-azole. Flucytosine may be added to amphotericin B.

Outcomes. Sterilization of the cerebrospinal fluid often pre-

cedes eradication of parenchymal infection. Thus, therapy

should be continued until normalization of all cerebrospinal

fluid analyses, normalization of radiological findings, and sta-

bilization of neurological function.

Evidence. Most data are based on observational reports of

use of amphotericin B. Liposomal amphotericin B was used

successfully in 5 of 6 cases of Candida meningitis in newborn

infants [117]. Because of its ability to penetrate the blood-brain

barrier, flucytosine has often been added [118]. Fluconazole

with flucytosine was used successfully in 1 case [119].

Values. Candida meningitis often follows candidemia in

newborn infants and has a high propensity for relapse. Un-

treated disease is lethal.Benefits, harms, and costs. Because of the high morbidity

and mortality of this infection, very aggressive therapy is

warranted.

Key recommendations. Amphotericin B (0.7–1 mg/kg/d)

plus flucytosine 25 mg/kg qid is appropriate as initial therapy

(BIII). The flucytosine dose should be adjusted to produce

serum levels of 40–60 mg/mL [79]. Very few data exist on flu-

conazole—it has been used as both followup therapy and sup-

pressive therapy. Because of the tendency for this disease to

relapse, therapy should be given for a minimum of 4 weeks

after resolution of all signs and symptoms related to the

infection.

Therapy of Candida meningitis associated with neurosurgicalprocedures should include removal of prosthetic material and

treatment of Candida meningitis as noted above [120].

Candidal Endophthalmitis

Objective. To resolve sight-threatening lesions.

Treatment options. Intravenous amphotericin B has most

often been used [121, 122]. Recent reports have also examined

oral or iv fluconazole [123]. Flucytosine has been used in com-

bination with amphotericin B. Vitrectomy may at times be

sight-saving. The role of intravitreal antifungal therapy is

unclear.Outcomes. Preservation of sight.

Evidence. Individual case reports and small case series have

demonstrated that amphotericin B, amphotericin B plus flu-

cytosine, and fluconazole may be effective. The role of vitrec-

tomy remains uncertain, but a recent study of C. albicans en-

dophthalmitis in injection drug abusers suggested that the

combination of early vitrectomy plus antifungal therapy was

most likely to lead to a good outcome with preservation of

vision [124]. Of additional interest is a recent National Eye

Institute–sponsored randomized study of therapy of bacterial

endophthalmitis in which initial pars plana vitrectomy with

intravitreal antibiotics followed by retap and reinjection of eyes

that did poorly after 36–60 h was compared with a strategy of initial anterior chamber and vitreous tap and/or biopsy [125].

For patients who presented with visual acuity of light percep-

tion only, initial vitrectomy tripled the chance of achieving 20/

40 or better acuity.

Values. Early aggressive therapy is critically important.De-

lays in diagnosis may lead to loss of vision.

Benefits, harms, and costs. Given the devastating conse-

quences of loss of sight, aggressive therapy is warranted.

Key recommendations. All patients with candidemia should

have a dilated retinal examination, preferably by an ophthal-




mologist (AII). The preponderance of clinical experience is with

amphotericin B, often combined with flucytosine (BIII). Recent

data also support the use of fluconazole for this indication,

particularly as followup therapy (BIII). The maximal doses

appropriate for other forms of invasive candidiasis would beappropriate and should maximize penetration into the eye.

Therapy should be continued until complete resolution of vis-

ible disease or convincing stabilization. Courses of 6–12 weeks

of therapy are typically required.

A diagnostic vitreal aspirate is generally recommended in

patients presenting with endophthalmitis of unknown origin.

If fungal elements are observed, some ophthalmologists instill

intravitreal amphotericin B. The utility of vitrectomy has not

been systematically studied. Extrapolation from a study of bac-

terial endophthalmitis [125] and from anecdotal experiences

with Candida endophthalmitis [124], initial vitrectomy and in-

travitreal amphotericin B may be most appropriate for patients

with substantial visual loss.

Nongenital Mucocutaneous Candidiasis

Oropharyngeal and Esophageal Candidiasis

Objective. To eliminate signs and symptoms of the disease

and to prevent recurrences.

Treatment options. Oropharyngeal candidiasis: topical az-

oles (clotrimazole troches), oral azoles (fluconazole, ketocon-

azole, or itraconazole), or oral polyenes (such as nystatin or

amphotericin B suspension) are usually effective. For refractory

or recurrent infections, orally administered and absorbed azoles

(ketoconazole, fluconazole, or itraconazole solution), ampho-tericin B suspension, or iv amphotericin B (only in azole-re-

fractory infections) may be used.

Esophageal candidiasis: topical therapy is ineffective. Azoles

(fluconazole or itraconazole solution) or iv amphotericin B

(necessary only in azole-refractory infections) are effective. In

patients who are unable to swallow, parenteral therapy should

be used.

Outcomes. Resolution of disease without recurrence.

Evidence. Oropharyngeal candidiasis: multiple randomized

prospective studies have been performed in both AIDS patients

and patients with cancer. Most patients will respond initially

to topical therapy [126–128]. In HIV-infected patients, symp-

tomatic relapses may occur sooner with topical therapy thanwith fluconazole [126], and resistance may develop with either

regimen [129]. Fluconazole is superior to ketoconazole [130].

Itraconazole capsules are equivalent in efficacy to ketoconazole

[131]. Itraconazole solution is better absorbed than the capsules

[132], and it is comparable in efficacy to fluconazole [133, 134].

Topical effects of oral solutions may be as important as effects

due to absorption [135, 136]. Recurrent infections typically oc-

cur in patients with immune suppression, especially AIDS.

Chronic suppressive therapy with fluconazole is effective in the

prevention of oropharyngeal candidiasis in both AIDS [18, 137]

and cancer patients [138]. In one study, chronic suppressive

therapy in HIV-infected patients reduced the relapse rate rel-

ative to intermittent therapy and was associated with similar

rates of development of microbiological resistance [18]. Oral

polyenes, such as amphotericin B or nystatin, are less effectiveat preventing this infection [139]. Approximately 64% of pa-

tients with fluconazole-refractory infections will respond to itra-

conazole solution [140]. Oral or iv amphotericin B is also ef-

fective in some patients [141].

Esophageal candidiasis: much of the information of the mi-

crobiology of esophageal candidiasis is extrapolated from stud-

ies of oropharyngeal candidiasis. However, it is known that, in

patients with either AIDS or esophageal cancer, C. albicans

remains the most common species isolated when candidal eso-

phagitis is present [142, 143]. The presence of oropharyngeal

candidiasis plus symptoms of esophagitis (dysphagia or odyn-

ophagia) is predictive of esophageal candidiasis [144]. A ther-

apeutic trial with fluconazole for patients with presumed esoph-ageal candidiasis is a cost-effective alternative to endoscopy;

most patients with esophageal candidiasis will have resolution

of their symptoms within 7 days after the start of therapy [145].

Fluconazole is superior to ketoconazole, itraconazole capsules,

and flucytosine for the treatment of esophageal candidiasis

[146–148]. Itraconazole capsules plus flucytosine is as effective

as fluconazole [149]. Itraconazole solution has efficacy com-

parable with that of fluconazole [150]. Up to 80% of patients

with fluconazole-refractory infections will respond to itracon-

azole solution [151]. Intravenous amphotericin B is also effec-

tive [152]. In patients with advanced AIDS, recurrent infections

are common [153] and chronic suppressive therapy with flu-

conazole (100 mg/d) is effective in preventing recurrence [154].

Both: the vast majority of infections are caused by C. albi-

cans, either alone or in mixed culture [127]. However, symp-

tomatic infections caused by C. glabrata and C. krusei alone

have been described [140]. Azole-refractory infections are as-

sociated with prior use of azoles, especially oral fluconazole,

and CD4 count !50/mm3 [155]. Antifungal susceptibility testing

has been shown to be predictive of clinical response to flucon-

azole and itraconazole [16]. In HIV-infected patients, use of

increasingly active antiretroviral therapy has been associated

with both declining rates of carriage of C. albicans and reduced

frequency of symptomatic episodes of oropharyngeal candi-

diasis [156].Values. The symptoms of oropharyngeal and esophageal

candidiasis may reduce oral intake of food and liquids and

significantly reduce the quality of life.

Benefits, harms, and costs. Maintenance of adequate nu-

trition and hydration is essential in immunocompromised hosts.

Many individuals have asymptomatic oropharyngeal coloni-

zation with Candida species, and treatment frequently does not

result in microbiological cure. Therefore, oropharyngeal fungal

cultures are of little benefit. Repeated courses of therapy or the

use of suppressive therapy for recurrent infections are major




risk factors for the development of an azole-refractory

infection.

Key recommendations. Oropharyngeal candidiasis: initial

episodes can be treated with clotrimazole troches (one 10-mg

troche 5 times daily) or nystatin (available as a suspension of 100,000 U/mL [4–6 mL q.i.d.] or as flavored 200,000 U pastilles

[one or two 4–5 times daily] for 7–14 days) (BII). Oral flucon-

azole (100 mg/d for 7–14 days orally) is as effective as and in

some studies superior to topical therapy (AI). Itraconazole so-

lution (200 mg/d for 7–14 days orally) is as efficacious as flu-

conazole (AI). Ketoconazole and itraconazole capsules are less

effective than fluconazole because of variable absorption (AI).

Suppressive therapy is effective for the prevention of recurrent

infections (AI), but to reduce the likelihood of development of

antifungal resistance, it should be used only if the recurrences

are frequent or disabling (IIB). Fluconazole-refractory oro-

pharyngeal candidiasis will respond to itraconazole (200 mg/

d orally, preferably as the solution) approximately two-thirdsof the time (AII). Amphotericin B oral suspension (1 mL q.i.d.

of the 100 mg/mL suspension) is sometimes effective in patients

who do not respond to itraconazole (BII). Anecdotal responses

of refractory disease to fluconazole solution (used in a swish-

and-swallow fashion) [136] and chewed itraconazole capsules

have also been noted. Intravenous amphotericin B (0.3 mg/kg/

d) is usually effective and may be used as a last resort in patients

with refractory disease (BII). Denture-related disease may re-

quire thorough disinfection of the denture for definitive cure

[157, 158].

Esophageal candidiasis: systemic therapy is required for ef-

fective treatment of esophageal candidiasis (BII). Although

symptoms of esophageal candidiasis may be mimicked by otherpathogens, a diagnostic trial of antifungal therapy is often ap-

propriate before endoscopy to search for other causes of eso-

phagitis (BII). A 14–21 day course of either fluconazole (100

mg/d orally) or itraconazole solution (200 mg/d orally) is highly

effective (AI). Ketoconazole and itraconazole capsules are less

effective than fluconazole because of variable absorption (AI).

Suppressive therapy should be used occasionally in patients

with disabling recurrent infections (AII). Fluconazole-refrac-

tory esophageal candidiasis should be treated with itraconazole

solution (200 mg/d orally) (AII). Intravenous amphotericin

B (0.3–0.7 mg/kg/d as needed to produce a response) may be

used in patients with otherwise refractory disease (BII).

Both: antifungal susceptibility testing is not generally needed

but can be useful in patients with refractory infection (BII). In

patients with AIDS, treatment of the underlying HIV infection

with highly active antiretroviral therapy (HAART) is critical

for prevention and management of these infections (BII).

Candida Onychomycosis

Although onychomycosis is usually caused by a dermato-

phyte, infections due to Candida species also occur [159]. Top-

ical agents are usually ineffective. For onychomycosis in gen-

eral, oral therapy with griseofulvin has largely been supplanted

by more-effective therapy with oral terbinafine or itraconazole

[160]. With respect to Candida onychomycosis, terbinafine has

only limited and unpredictable in vitro activity [161, 162] andhas not demonstrated consistently good activity in clinical trials

[163]. Although the number of reported cases is small, therapy

with itraconazole does appear to be effective [164, 165]. Ther-

apy with itraconazole (200 mg b.i.d. for a week, repeated

monthly for 3–4 months) appears most appropriate (AII).

Candidal Skin Infections and Paronychia

Nonhematogenous primary skin infections typically occur

as intertrigo in skin folds, especially in obese and diabetic pa-

tients. Topical azoles and polyenes, including clotrimazole,

miconazole, and nystatin, are effective. Keeping the area dry

is also important. For paronychia, the most important aspectis drainage.

Chronic Mucocutaneous Candidiasis

The persistent immunological defect of chronic mucocuta-

neous candidiasis requires a long-term approach that is anal-

ogous to that used in AIDS patients with rapidly relapsing

oropharyngeal candidiasis. Systemic therapy is needed, and all

of the azole antifungal agents (ketoconazole, fluconazole, and

itraconazole) have been used successfully [166, 167]. The re-

quired dosages are similar to those used for other forms of

mucocutaneous candidiasis. As with HIV-infected patients, de-

velopment of resistance to these agents has also been described

[168, 169].

Genital Candidiasis

Objective. To achieve rapid and complete relief of signs

and symptoms of vulvovaginal inflammation and to prevent

recurrences.

Treatment options. Topical agents including azoles (all are

used for 1–7 days depending on risk classification: clotrimazole

[over the counter {OTC}], butoconazole [OTC], miconazole

[OTC], tioconazole [OTC], terconazole), nystatin 100,000 U

–14 d, oral azoles (ketoconazole 500 mg ddaily 7 b.i.d. 5(not approved in the United States); itraconazole 200 mg

d or 200 mg d (not approved in the Unitedb.i.d. 1 q.d. 3

States); fluconazole 150 dose [170]. Boric acid (600 mgmg 1

in a gelatin capsule, 1 daily per d) is also effectivevagina 14

[171].

Outcomes. Resolution of signs and symptoms of vaginitis

in 48–72 h; mycological cure in 4–7 days.

Evidence. Multiple double-blind randomized studies [2,

170].

Values. Highly effective relief of symptoms that are asso-




Table 3. Classification of candidal vaginitis.

Feature Uncomplicateda

Complicatedb

Severity Mild or moderate Severe

Frequency Sporadic Recurrent

Organism Candida albicans Non-albicans species

of Candida

Host Normal Abnormal (uncontrolled

diabetes mellitus)

NOTE. Patients with vaginitis can be classified as having uncomplicated

disease (90% of patients) or complicated disease (∼10% of patients).a

Patients with all of these features are defined as having uncomplicated

vaginitis.b

Patients with any of these features are defined as havingcomplicated vaginitis

[173].

ciated with substantial morbidity can be achieved promptly

with current therapies.

Benefits, harms, and costs. Self-diagnosis of yeast vaginitis

is unreliable. Incorrect diagnosis results in overuse of topical

antifungal agents with subsequent risk of contact and irritantvulvar dermatitis.

Key recommendations. Vaginal candidiasis may be classi-

fied into complicated and uncomplicated forms (table 3) [172].

Uncomplicated vaginitis is seen in 90% of patients and responds

readily to short-course oral or topical treatment with any of

the therapies listed above, including the single-dose regimens

(AI). In contrast, the complicated vaginitis seen in ∼10% of

patients requires antimycotic therapy for 7 days (BIII). Azole

therapy is unreliable for non-albicans species of Candida (BIII).

C. glabrata and the other non-albicans infections frequently

respond to topical boric acid 600 days (BII) or top-mg/d 14

ical flucytosine (BII). Azole-resistant C. albicans infections are

extremely rare [173].Recurrent vaginitis is usually due to azole-susceptible C. al-

bicans. After control of causal factors (e.g., uncontrolled dia-

betes), induction therapy with 2 weeks of a topical or oral azole

should be followed by a maintenance regimen for 6 months.

Suitable maintenance regimens include fluconazole (150 mg

orally every week), ketoconazole (100 mg q.d.) [174], itracon-

azole (100 mg q.o.d.) or daily therapy with any topical azole

(AII).

Prophylaxis

HIV-Infected Patients

See the subsection Oropharyngeal and Esophageal Candi-

diasis in the Nongenital Mucocutaneous Candidiasis section.

Neutropenic Patients

Objective. To prevent development of invasive fungal in-

fections during periods of risk.


fluconazole. (Note added in proof: Pending results of ongoing

trials, the recently licensed iv form of itraconazole may provide

an additional therapeutic option).

Outcomes. Prevention of onset of signs and symptoms of

invasive candidiasis.Evidence. Randomized, prospective,placebo-controlled tri-

als have shown that systemically active antifungal agents can

reduce the rate of development of invasive Candida infections

in high-risk patients. The best data have compared fluconazole

at 400 mg/d with placebo in bone-marrow transplant recipients

[175, 176]. The utility of other potentially active agents

(amphotericin B, itraconazole) may be limited by toxicity or

bioavailability.

Values. Prevention of invasive fungal infection would pre-

sumably lower morbidity [177]. Observed effects on overall

mortality have either been none [176] or beneficial [175], but

both studies did demonstrate a reduction in the rate of fungal-

associated deaths.

Benefits, harms, and costs. Inappropriate use of prophylaxis

in low-risk patient populations could apply epidemiologicalpressure that could select for resistant organisms.

Key recommendations. Fluconazole at 400 mg/d during the

period of neutropenia is warranted in patients who are at sig-

nificant risk of invasive candidiasis (AI). Such patient groups

include selected patients receiving standard chemotherapy for

acute myelogenous leukemia, allogeneic bone-marrow trans-

plants, or high-risk autologous bone-marrow transplants. How-

ever, in this context, it is important to understand that, among

these populations, chemotherapy or bone-marrow transplant

protocols do not all produce equivalent risk and that local

experience with particular chemotherapy and cytokine regimens

should be used to determine the relevance of prophylaxis [178].

Solid-Organ Transplantation

Objective. To prevent development of invasive fungal in-

fections during periods of risk.


fluconazole.

Outcomes. Prevention of onset of signs and symptoms of

invasive candidiasis.

Evidence. Patients undergoing liver transplantation who

have 2 of a group of key risk factors (retransplantation, cre-

atinine of 12.0 mg/dL, choledochojejunostomy, intraoperative

use of 40 units of blood products, fungal colonization de-tected within the first 3 days after transplantation) have been

identified as being at high risk for invasive fungal infections,

especially invasive candidiasis [179–181]. In prospective ran-

domized studies, amphotericin B deoxycholate (10–20 mg/d),

liposomal amphotericin B (AmBisome, 1 mg/kg/d), and flu-

conazole (400 mg/d) may have reduced both fungal colonization

and the risk of serious Candida infections [182–184].

The risk for candidiasis following pancreatic transplantation

may be comparable to that following liver transplantation. A

recent retrospective review of 445 consecutive pancreatic trans-




plant recipients revealed a 6% frequency of intra-abdominal

fungal infections in those who received fluconazole prophylaxis

(400 mg/d) for 7 days after transplantation, compared with 10%

for those without prophylaxis [185]. There also was significant

improvement of 1-year graft survival rate and overall survivalin patients who had no infection. Prospective and case-con-

trolled studies will further help to delineate the population of

patients at high risk for invasive candidiasis and the potential

benefits of fluconazole prophylaxis.

The risk of invasive candidiasis following transplantation of

other solid organs appears to be too low to warrant systemic

prophylaxis.

Values. Prevention of the significant morbidity associated

with invasive candidiasis is warranted.

Benefits, harms, and costs. Injudicious use of prophylaxis

in low-risk settings might lead to selection of resistant

organisms.

Key recommendations. High-risk liver transplant recipientsshould receive prophylactic antifungal therapy during the early

postoperative period (AI).

Acknowledgments

We thank Dr. Andreas Groll, National Cancer Institute, and Dr.

Scott Whitcupp, National Eye Institute, for their review of selected

sections of these guidelines.

References

1. Pfaller MA, Jones RN, Messer SA, Edmond MB, Wenzel RP, SCOPE Par-

ticipant Group. National surveillance of nosocomial blood stream in-fection due to species of Candida other than Candida albicans: frequency

of occurrence and antifungal susceptibility in the SCOPE program.

Diagn Microbiol Infect Dis 1998;30:121–9.

2. Sobel JD. Vaginitis. N Engl J Med 1997;337:1896–903.

3. National Committee for Clinical Laboratory Standards (NCCLS). Refer-

ence method for broth dilution antifungal susceptibility testing of yeasts:

approved standard. NCCLS document M27-A. Wayne, PA: NCCLS,

1997.

4. Rex JH, Cooper CR Jr, Merz WG, Galgiani JN, Anaissie EJ. Detection of

amphotericin B–resistant Candida isolates in a broth-based system. An-

timicrob Agents Chemother 1995;39:906–9.

5. Rex JH, Pfaller MA, Barry AL, et al. Antifungal susceptibility testing of

isolates from a randomized, multicenter trial of fluconazole vs. ampho-

tericin B as treatment of non-neutropenic patients with candidemia. An-

timicrob Agents Chemother1995

;39:40–4.6. Pfaller MA, Bale MJ, Buschelman B, Rhomberg P. Antifungal activity of

a new triazole, D0870, compared with four other antifungalagents tested

against clinical isolates of Candida and Torulopsis glabrata. Diagn Mi-

crobiol Infect Dis 1994;19:75–80.

7. Martinez-Suarez JV, Rodriguez-Tudela JL. Patterns of in vitro activity of

itraconazole and imidazole antifungal agents against Candida albicans

with decreased susceptibility to fluconazole from Spain. Antimicrob

Agents Chemother 1995;39:1512–6.

8. Nguyen MH, Clancy CJ, Yu VL, et al. Do in vitro susceptibilityd ata predict

the microbiologic response to amphotericin B? Results of a prospective

study of patients with candida fungemia. J Infect Dis 1998;177:425–30.

9. Wanger A, Mills K, Nelson PW, Rex JH. Comparison of Etest and National

Committee for Clinical Laboratory Standards broth macrodilution

method for antifungal susceptibility testing: enhanced ability to detect

amphotericin B–resistant Candida isolates. Antimicrob Agents Chem-

other 1995;39:2520–2.

10. Rex JH, Lozano-Chiu M, Paetznick V, et al. Susceptibility testing of currentCandida bloodstream isolates from Mycoses Study Group (MSG) col-

laborative study #34: isolates of C. krusei are often resistant to both

fluconazole and amphotericin B [abstract 324]. Clin Infect Dis 1998;27:

981.

11. Fisher MA, Shen S-H, Haddad J, Tarry WF. Comparison of in vivo activity

of fluconazole with that of amphotericin B against Candida tropicalis,

Candida glabrata, and Candida krusei . Antimicrob Agents Chemother

1989;33:1443–6.

12. Karyotakis NC, Anaissie EJ, Hachem R, Dignani MC, Samonis G. Com-

parison of the efficacy of polyenes and triazoles against hematogenous

Candida krusei infection in neutropenic mice. J Infect Dis 1993;168:

1311–3.

13. Pfaller MA, Messer SA, Hollis RJ. Strain delineation and antifungal sus-

ceptibilities of epidemiologically related and unrelated isolates of Can-

dida lusitaniae. Diagn Microbiol Infect Dis 1994;20:127–33.

14. Yoon SA, Vazquez JA, Steffan PE, Sobel JD, Akins RA. High-frequency,

in vitro reversible switching of Candida lusitaniae clinical isolates from

amphotericin B susceptibility to resistance. Antimicrob Agents Chem-

other 1999;43:836–45.

15. Marr KA, White TC, van Burik J-AH, Bowden RA. Development of flu-

conazole resistance in Candida albicans causing disseminated infection

in a patient undergoing marrow transplantation. Clin Infect Dis 1997;

25:908–10.

16. Rex JH, Pfaller MA, Galgiani JN, et al. Development of interpretivebreak-

points for antifungal susceptibility testing: conceptual framework and

analysis of in vitro–in vivo correlation data for fluconazole, itraconazole,

and Candida infections. Clin Infect Dis 1997;24:235–47.

17. Clancy CJ, Kauffman CA, Morris A, et al. Correlation of fluconazole MIC

and response to therapy for patients with candidemia due to C. albicans

and non–C. albicans spp.: results of a multicenter prospective study of

candidemia [abstract 98]. Clin Infect Dis 1998;27:938.18. Revankar SG, Kirkpatrick WR, McAtee RK, et al. A randomized trial of

continuous or intermittent therapy with fluconazole for oropharyngeal

candidiasis in HIV-infected patients: clinical outcomes and development

of fluconazole resistance. Am J Med 1998;105:7–11.

19. Clancy CJ, Nguyen MH. Correlation between in vitro susceptibility deter-

mined by E test and response to therapy with amphotericin B: results

from a multicenter prospective study of candidemia. Antimicrob Agents

Chemother 1999;43:1289–90.

20. Clancy CJ, Nguyen MH. Correlation between in vitro susceptibility deter-

mined by E test and response to therapy with amphotericin B: results

from a multicenter prospective study of candidemia. Antimicrob Agents

Chemother 1999;43:1289–90.

21. Swenson CE, Perkins WR, Roberts P, et al. In vitro and in vivo antifungal

activity of amphotericin B lipid complex: are phospholipases important?

Antimicrob Agents Chemother1998

;42:767–71.22. Walsh TJ, Hiemenz JW, Seibel NL, et al. Amph otericin B lipid complex for

invasive fungal infections: analysis of safety and efficacy in 556 cases.

Clin Infect Dis 1998;26:1383–96.

23. Bowden RA, Cays M, Gooley T, Mamelok RD, van Burik JA. Phase 1

study of amphotericin B colloidal dispersion for the treatment of invasive

fungalinfections aftermarrow transplant.J InfectDis 1996;173:1208–15.

24. Noskin GA, Pietrelli L, Coffey G, Gurwith M, Liang L-J. Amphotericin B

colloidal dispersion for the treatment of candidemia in immunocom-

promised patients. Clin Infect Dis 1998;26:461–7.

25. Hiemenz JW, Walsh TJ. Lipid formulations of amphotericin B: recent pro-

gress and future directions. Clin Infect Dis 1996;22(Suppl 2):S133–44.




26. Rex JH, Walsh TJ, Anaissie EA. Fungal infections in iatrogenically com-

promised hosts. Adv Intern Med 1998;43:321–71.

27. Clemons KV, Stevens DA. Comparison of Fungizone, Amphotec, Am-

Bisome, and Abelcet for treatment of systemic murine cryptococcosis.

Antimicrob Agents Chemother 1998;42:899–902.

28. Groll A, Giri N, Gonzalez C, et al. Penetration of lipid formulations of amphotericin B into cerebrospinal fluid and brain tissue [abstract A-90].

In: Program and abstracts of the 37th Interscience Conference on An-

timicrobial Agents and Chemotherapy (Toronto, Canada). Washington,

DC: American Society for Microbiology, 1997.

29. Dismukes WE. Introduction to antifungal drugs. Clin Infect Dis 2000;30:

653–7 (in this issue).

30. Groll A, Walsh TJ. Pharmacology of antifungal compounds. Adv Phar-

macol 1998;44:343–500.

31. van den Anker JN, van Popele NM, Sauer PJ. Antifungal agents in neonatal

systemic candidiasis. Antimicrob Agents Chemother 1995;39:1391–7.

32. Walsh TJ, Whitcomb P, Piscitelli S, et al. Safety, tolerance, and pharma-

cokinetics of amphotericin B lipidcomplex in children withhepatosplenic

candidiasis. Antimicrob Agents Chemother 1997;41:1944–8.

33. Baley JE, Meyers C, Kliegman RM, Jacobs MR, Blumer JL. Pharmaco-

kinetics, outcome of treatment, and toxic effects of amphotericin B and

5-fluorocytosine in neonates. J Pediatr 1990;116:791–7.

34. Lee JW, Seibel NI, Amantea MA, Whitcomb P, Pizzo PA, Walsh TJ. Safety,

tolerance, and pharmacokinetics of fluconazole in children with neo-

plastic diseases. J Pediatr 1992;120:987–93.

35. Brammer KW, Coates PE. Pharmacokinetics of fluconazole in pediatric

patients. Eur J Clin Microbiol Infect Dis 1994;13:325–9.

36. Saxen H, Hoppu K, Pohjavuori M. Pharmacokinetics of fluconazole in very

low birth weight infants during the first two weeks of life.Clin Pharmacol

Ther 1993;54:269–77.

37. Seay RE, Larson TA, Toscano JP, Bostrom BC, O’Leary MC, Uden DL.

Pharmacokinetics of fluconazole in immune-compromised children with

leukemia or other hematologic disease. Pharmacotherapy 1995;15:52–8.

38. Grant SM, Clissold SP. Fluconazole: areview of its pharmacodynamic and

pharmacokinetic properties and therapeutic potential in superficial and

systemic mycoses. Drugs 1990;39:877–916.

39. Fasano C, O’Keefe J, Gibbs D. Fluconazole treatment of neonates andinfants with severe fungal infections not treatable with conventional

agents. Eur J Clin Microbiol Infect Dis 1994;13:351–4.

40. de Repentigny L, Ratelle J, Leclerc JM, et al. Repeated-dose pharmaco-

kinetics of an oral solution of itraconazole in infants and children. An-


41. Walsh TJ, McEvoy M, Rishforth B, et al. Cyclodextrin itraconazole in the

treatment of oropharyngeal candidiasis in pediatric patients with HIV

infection [abstract J-145]. In: Program and abstracts of the 38th Inter-

science Conference on Antimicrobial Agents and Chemotherapy (San

Diego). Washington, DC: American Society for Microbiology, 1998.

42. Sobel JD. Practice guidelines for the treatment of fungal infections. Clin

Infect Dis 2000;30:652 (in this issue).

43. Boogaerts J, Michaux J-L, Bosly A, et al. Pharmacokinetics and safety of

seven days of intravenous (IV) itraconazole followed by two weeks oral

itraconazole solution in patients with haematological malignancy [ab-stract A87]. In: Program and abstracts of the 36th Interscience Confer-

ence on Antimicrobial Agents and Chemotherapy, 1996.

44. Vandewoude K, Vogelaers D, Decruyenaere J, et al. Concentrations in

plasma and safety of 7 days of intravenous itraconazole followed by 2

weeks of oral itraconazole solution in patients in intensive care units.

Antimicrob Agents Chemother 1997;41:2714–8.

45. Zhou HH, Goldman M,Wu J, etal. A pharmacokineticstudyof intravenous

itraconazole followed by oral administration of itraconazole capsules in

patients with advanced human immunodeficiency virus infection. J Clin

Pharmacol 1998;38:593–602.

46. Wey SB, Mori M, Pfaller MA, Woolson RF, Wenzel RP. Hospital acquired

candidemia: the attributable mortality and excess length of stay. Arch

Intern Med 1988;148:2642–5.

47. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing flu-

conazole with amphotericin B for the treatment of candidemia in patients

without neutropenia. N Engl J Med 1994;331:1325–30.

48. Phillips P, Shafran S, Garber G, et al. Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-

neutropenic patients. Eur J Clin Microbiol Infect Dis 1997;16:337–45.

49. Anaissie EJ, Rex JH, Uzun O, Vartivarian S. Predictors of adverse outcome

in cancer patients with candidemia. Am J Med 1998;104:238–45.

50. Nguyen MH, Peacock JE Jr, Tanner DC, et al. Therapeutic approaches in

patients with candidemia: evaluation in a multicenter, prospective, ob-

servational study. Arch Intern Med 1995;155:2429–35.

51. Anaissie EJ, White M, Uzun O, et al. Amphotericin B lipid complex (ABLC)

versus amphotericin B (AMB) for treatment of hematogenous and in-

vasive candidiasis: a prospective, randomized, multicenter trial [abstract

LM21]. In: Program and abstracts of the 35th Interscience Conference

on Antimicrobial Agents and Chemotherapy (San Francisco). Washing-

ton, DC: American Society for Microbiology, 1995.

52. Levy I, Rubin LG, Vasishtha S, Tucci V, Sood SK. Emergence of Candida

parapsilosis as the predominant species causing candidemia in children.


53. Kossoff EH, Buescher ES, Karlowicz MG. Candidemia in a neonatal in-

tensive care unit: trends during fifteen years and clinical features of 111

cases. Pediatr Infect Dis J 1998;17:504–8.

54. Coleman DC, Rinaldi MG, Haynes KA, et al. Importance of Candida spe-

cies other than Candida albicans as opportunistic pathogens. Med Mycol

1998;36:156–65.

55. Rex JH, Bennett JE, Sugar AM, et al. Intravascular catheter exchanges and

the duration of candidemia. Clin Infect Dis 1995;21:994–6.

56. Edwards JE Jr, Bodey GP, Bowden RA, et al. International conference for

the development of a consensus on the management and prevention of

severe candidal infections. Clin Infect Dis 1997;25:43–59.

57. Hughes WT, Armstrong D, Bodey GP, et al. 1997 guidelines for the use of

antimicrobial agents in neutropenic patients with unexplained fever. Clin

Infect Dis 1997;25:551–73.

58. Pittet D, Monod M, Suter PM, Frenk E, Auckenthaler R. Candida colo-nization and subsequent infections in critically ill surgical patients. Ann

Surg 1994;220:751–8.

59. Wey SB, Mori M, Pfaller MA, Woolson RF, Wenzel RP. Risk factors for

hospital-acquired candidemia: a matched case-control study.Arch Intern

Med 1989;149:2349–53.

60. Fraser VJ, Jones M, Dunkel J, Storfer S, Medoff G, Dunagan WC. Can-

didemia in a tertiary care hospital: epidemiology, risk factors, and pre-

dictors of mortality. Clin Infect Dis 1992;15:414–21.

61. Boogaerts M, Garber G, Winston D, et al. Itraconazole compared with

amphotericin B as empirical therapy for persistent fever of unknown

origin in neutropenic patients. Bone Marrow Transplant 1999;23(Suppl

1):S111.

62. Michallet M, Persat F, Kranzhofer N, et al. Pharmacokinetics of itracon-

azole oral solution in allogeneic bone marrow transplant patients

receiving total body irradiation. Bone Marrow Transplant1998

;21:1239–43.

63. Menichetti F, Del Favero A, Martino P, et al. Itraconazole oral solution as

prophylaxis for fungal infections in neutropenic patients with hemato-

logic malignancies: a randomized, placibo-controlled, double-blind, mul-

ticenter trial. Clin Infect Dis 1999;28:250–5.

64. Pizzo PA, Robichaud KJ, Gill FA, Witebsky FG. Empiric antibiotics and

antifungal therapy for cancer patients with prolonged fever and gran-

ulocytopenia. Am J Med 1982;72:101–11.

65. EORTC International Antimicrobial Therapy Cooperative Group. Empiric

antifungal therapy in febrile granulocytopenic patients. Am J Med

1989;86:668–72.




66. Walsh TJ, Lee J, Lecciones J, Rubin M, Butler K,Francis P. Empirictherapy

with amphotericin B in febrile granulocytopenic patients. Rev Infect Dis

1991;13:496–503.

67. Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for em-

pirical therapy in patients with persistent fever and neutropenia. N Engl

J Med1999

;340:764–71.68. Thaler M, Pastakia B, Shawker TH, O’Leary T, Pizzo PA. Hepatic candi-

diasis in cancer patients: the evolving picture of the syndrome. Ann

Intern Med 1988;108:88–100.

69. Walsh T, Whitcomb PO, Ravankar S, Shannon K, Alish S, Pizzo PA. Suc-

cessful treatment of hepatosplenic candidiasis through repeated episodes

of neutropenia. Cancer 1995;76:2357–62.

70. Kauffman CA, Bradley SF, Ross SC, Weber DR. Hepatospleniccandidiasis:

successful treatment with fluconazole. Am J Med 1991;91:137–41.

71. Anaissie E, Bodey GP, Kantarjian H, et al. Fluconazole therapy for chronic

disseminated candidiasis in patients with leukemia and prior amphoter-

icin B therapy. Am J Med 1991;91:142–50.

72. Kam LA, Giacoia GP. Congenital cutaneous candidiasis. Am J Dis Child

1975;129:1215–8.

73. Faix RG. Invasive neonatal candidiasis: comparison of albicans and par-

apsilosis infection. Pediatr Infect Dis J 1992;11:88–93.

74. Wise GJ, Silver DA. Fungal infections of the genitourinary system. J Urol

1993;149:1377–88.

75. Hamory BH, Wenzel RP. Hospital-associated candiduria: predisposing fac-

tors and review of the literature. J Urol 1978;120:444–8.

76. Sobel JD, Kauffman CA, McKinsey D, et al. Candiduria: a randomized,

double-blind study oftreatmentwith fluconazole and placebo. ClinInfect

Dis 2000;30:19–24.

77. Ang BSP, Telenti A, King B, Steckelberg JM, Wilson WR. Candidemia from

a urinary tract source: microbiological aspects and clinical significance.


78. Jacobs LG, Skidmore EA, Freeman K, Lipschultz D, Fox N. Oral flucon-

azole compared with bladder irrigation with amphotericin B for treat-

ment of fungal urinary tract infections in elderly patients. Clin Infect

Dis 1996;22:30–5.

79. Francis P, Walsh TJ. Evolving role of flucytosine in immunocompromised

patients: new insights into safety, pharmacokinetics, and antifungal ther-apy. Clin Infect Dis 1992;15:1003–18.

80. Leu H-S, Huang C-T. Clearance of funguria with short-course antifungal

regimens: a prospective, randomized, controlled study. Clin Infect Dis

1995;20:1152–7.

81. Fong IW, Cheng PC, Hinton NA. Fungicidal effect of amphotericin B in

urine: in vitro study to assess feasibility of bladder washout for locali-

zation of site of candiduria. Antimicrob Agents Chemother 1991;35:

1856–9.

82. Haron E, Vartivarian S, Anaissie E, Dekmezian R, Bodey GP. Primary

Candida pneumonia: experience at a large cancer center and review of

the literature. Medicine (Baltimore) 1993;72:137–42.

83. Panos RJ, Barr LF, Walsh TJ, Silverman HJ. Factors associated with fatal

hemoptysis in cancer patients. Chest 1988;94:1008–13.

84. Masur H, Rosen PP, Armstrong D. Pulmonary disease caused by Candida

species. Am J Med1977

;63:914–25.85. El-Ebiary M, Torres A, Fabrega N, et al. Significance of the isolation of

Candida species from respiratory samplesin criticallyill,non-neutropenic

patients. Am J Respir Crit Care Med 1997;156:583–90.

86. Walsh TJ, Gray W. Candida epiglottitis in immunocompromised patients.

Chest 1987;91:482–5.

87. Wang JN, Liu CC, Huang TZ, Huang SS, Wu JM. Laryngeal candidiasis

in children. Scand J Infect Dis 1997;29:427–9.

88. Fisher EW, Richards A, Anderson G, Albert DM. Laryngeal candidiasis:

a cause of airway obstruction in the immunocompromised child. J Lar-

yngol Otol 1992;106:168–70.

89. Almekinders LC, Greene WB. Vertebral Candida infections: a case report

and review of the literature. Clin Orthop 1991;267:174–8.

90. Ferra C, Doebbeling BN, Hollis RJ, Pfaller MA, Lee CK, Gingrich RD.

Candida tropicalis vertebral osteomyelitis: a late sequela of fungemia.


91. Hennequin C, Bouree P, Hiesse C, Dupont B, Charpentier B. Spondylo-

diskitis due to Candida albicans: report of two patients who were suc-

cessfully treated with fluconazole and review of the literature. Clin InfectDis 1996;23:176–8.

92. Sugar AM, Saunders C, Diamond RD. Successful treatment of Candida

osteomyelitis with fluconazole: a noncomparative study of two patients.

Diagn Microbiol Infect Dis 1990;13:517–20.

93. Tang C. Successful treatment of Candida albicans osteomyelitis with flu-

conazole. J Infect 1993;26:89–92.

94. Weers-Pothoff G, Havermans JF, Kamphuis J, Sinnige HA, Meis JF. Can-

dida tropicalis arthritis in a patient with acute myeloid leukemia suc-

cessfully treated with fluconazole: casereport and review of the literature.

Infection 1997;25:109–11.

95. Tunkel AR, Thomas CY, Wispelwey B. Candida prosthetic arthritis: report

of a case treated with fluconazole and review of the literature. Am J

Med 1993;94:100–3.

96. Clancy CJ, Nguyen MH, Morris AJ. Candidal mediastinitis: an emerging

clinical entity. Clin Infect Dis1997

;25:608–13.97. Goldie SJ, Kiernan-Tridle L, Torres C, et al. Fungal peritonitis in a large

chronic peritoneal dialysis population: a report of 55 episodes. Am J

Kidney Dis 1996;28:86–91.

98. Eisenberg ES, Leviton I, Soeiro R. Fungal peritonitis in patients receiving

peritoneal dialysis: experience with 11 patients and review of the liter-

ature. Rev Infect Dis 1986;8:309–21.

99. Levine J, Bernard DB, Idelson BA, Farnham H, Saunders C, Sugar AM.

Fungal peritonitis complicating continuous ambulatory peritoneal di-

alysis: successful treatment with fluconazole, a new orally active anti-

fungal agent. Am J Med 1989;86:825–9.

100. Michel C, Courdavault L, al Khayat R, Viron B, Roux P, Mignon F. Fungal

peritonitis in patients on peritoneal dialysis. Am J Nephrol 1994;14:

113–20.

101. Bayer AS, Blumenkrantz MJ, Montgomerie JZ, Galpin JE, Coburn JW,

Guze LB. Candida peritonitis: report of 22 cases and review of the Eng-

lish literature. Am J Med 1976;61:832–40.

102. Solomkin JS, Flohr AB, Quie PG, Simmons RL. The role of Candida in

intraperitoneal infections. Surgery 1980;88:524–30.

103. Calandra T, Bille J, Schneider R, Mosimann F, Francioli P. Clinical signif-

icance of Candida isolated from peritoneum in surgical patients. Lancet

1989;2:1437–40.

104. Eggimann P, Francioli P, Bille J, et al. Fluconazole prophylaxis prevents

intra-abdominal candidiasis in high-risk surgical patients. Crit CareMed

1999;27:1066–72.

105. Adamson PC, Rinaldi MG, Pizzo PA, Walsh TJ. Amphotericin B in treat-

ment of Candida cholecystitis. Pediatr Infect Dis J 1989;8:408–11.

106. Muehrcke DD, Lytle BW, Cosgrove DM 3d. Surgical and long-term anti-

fungal therapy for fungal prosthetic valveendocarditis. Ann ThoracSurg

1995;60:538–43.

107. Schrank JH Jr, Dooley DP. Purulent pericarditis caused by Candida species:

case report and review. Clin Infect Dis 1995;21:182–7.

108. Berg RA, Stein JM. Medical management of fungal suppurative thrombosis

of great central veins in a child. Pediatr Infect Dis J 1989;8:469–70.

109. Strinden WD, Helgerson RB, Maki DG. Candida septic thrombosis of the

great central veins associated with central catheters. Ann Surg 1985;202:

653–8.

110. Jarrett F, Maki DG, Chan C-K. Management of septic thrombosis of the

inferior vena cava caused by Candida. Arch Surg 1978;113:637–9.

111. Walsh TJ, Bustamente CI, Vlahov D, Standiford HC. Candidal suppurative

peripheral thrombophlebitis: recognition, prevention, and management.

Infect Control 1986;7:16–22.

112. Walsh TJ, Hutchins GM, Bulkley BH, Mendelsohn G. Fungal infections




of the heart: an analysis of 51 autopsied patients. Am J Cardiol 1980;

45:357–66.

113. Johnston P, Lee J, Demanski M, et al. Late recurrent Candida endocarditis.

Chest 1991;99:1531–3.

114. Baddour LM. Long-term suppressive therapy for Candida parapsilosis –

induced prosthetic valve endocarditis. Mayo Clin Proc1995

;70:773–5.115. Castiglia M, Smego RA, Sames EL. Candida endocarditis and amphotericin

B intolerance: potential role for fluconazole. Infect Dis Clin Pract1994;3:

248–53.

116. Rabinovici R, Szewczyk D, Ovadia P, Greenspan JR, Sivalingam JJ. Can-

dida pericarditis: clinical profile and treatment. Ann Thorac Surg

1997;63:1200–4.

117. Scarcella A, Pasquariello MB, Giugliano B, Vendemiia M, De Lucia A.

Liposomal amphotericin B treatment for neonatal fungal infections. Pe-

diatr Infect Dis J 1998;17:146–8.

118. Smego RA Jr, Perfect JR, Durack DT.Co mbined therapy with amphotericin

B and 5-fluorocytosine for Candida meningitis. Rev Infect Dis 1984; 6:

791–801.

119. Marr B, Gross S, Cunningham C, Weiner L. Candidal sepsis and meningitis

in a very-low-birth-weight infant successfully treated with fluconazole

and flucytosine. Clin Infect Dis 1994;19:795–6.

120. Nguyen MH, Yu VL. Meningitis caused by Candida species: an emerging

problem in neurosurgical patients. Clin Infect Dis 1995;21:323–7.

121. Edwards JE Jr, Foos RY, Montgomerie JZ, Guze LB. Ocular manifestations

of Candida septicemia: review of seventy-six cases of hematogenous Can-

dida endophthalmitis. Medicine (Baltimore) 1974;53:47–75.

122. Meyers BR, Lieberman TW, Ferry AP. Candida endophthalmitis compli-

cating candidemia. Ann Intern Med 1973;79:647–53.

123. Akler ME, Vellend H, McNeely DM, Walmsley SL, Gold WL. Use of

fluconazole in the treatment of candidal endophthalmitis. Clin InfectDis

1995;20:657–64.

124. Martinez-Vasquez C, Fernandez-Ulloa J, Bordon J, et al. Candida albicans

endophthalmitis in brown heroin addicts: response to early vitrectomy

preceded and followed by antifungal therapy. Clin Infect Dis 1998;27:

1130–3.

125. Endophthalmitis Vitrectomy Study Group. Results of the Endophthalmitis

Vitrectomy Study: a randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial en-

dophthalmitis. Arch Ophthalmol 1995;113:1479–96.

126. Pons V, Greenspan D, Debruin M, the Multicenter Study Group. Therapy

for oropharyngeal candidiasis in HIV-infected patients: a randomized,

prospective multicenter study of oral fluconazole versus clotrimazole

troches. J Acquir Immune Defic Syndr 1993;6:1311–6.

127. Sangeorzan JA, Bradley SF, He X, et al. Epidemiology of oral candidiasis

in HIV-infected patients: colonization, infection, treatment, and emer-

gence of fluconazole resistance. Am J Med 1994;97:339–46.

128. Finlay PM, Richardson MD, Robertson AG. A comparative study of the

efficacy of fluconazole and amphotericin B in the treatment of oro-

pharyngeal candidosis in patients undergoing radiotherapy for head and

neck tumours. Br J Oral Maxillofac Surg 1996;34:23–5.

129. Pelletier R, Peter J, Antin C, Gonzalez C, Wood L, Walsh TJ. Emergence

of resistance of Candida albicans to clotrimazole in human immuno-deficiency virus–infected children: in vitro and clinical correlations. J

Clin Microbiol 2000;38:1563–8.

130. De Wit S, Weerts D, Goossens H, Clumeck N. Comparison of fluconazole

and ketoconazole for oropharyngeal candidiasis in AIDS.Lancet 1989;1:

746–8.

131. Blatchford NR. Treatment of oral candidosis with itraconazole: a review. J

Am Acad Dermatol 1990;23:565–7.

132. Cartledge JD, Midgely J, Gazzard BG. Itraconazole solution: higher serum

drug concentrations and better clinical response rates than the capsule

formulation in acquired immunodeficiency syndrome patients with can-

didosis. J Clin Pathol 1997;50:477–80.

133. Graybill JR, Vazquez J, Darouiche RO, et al. Randomized trial of itracon-

azole oral solution for oropharyngeal candidiasis in HIV/AIDS patients.

Am J Med 1998;104:33–9.

134. Phillips P, De Beule K, Frechette G, et al. A double-blind comparison of

itraconazole oral solution and fluconazole capsules for the treatment of

oropharyngeal candidiasis in patients with AIDS. Clin Infect Dis 1998;

26:1368–73.135. Mascarenas CA, Hardin TC, Pennick GJ, Rinaldi MG, Graybill JR. Treat-

ment of thrush with itraconazole solution: evidence for topical effect.


136. Martins MD, Rex JH. Fluconazole suspension for oropharyngeal candi-

diasis unresponsive to tablets. Ann Intern Med 1997;126:332–3.

137. Powderly WG, Finkelstein DM, Feinberg J, et al. A randomized trial com-

paring fluconazole with clotrimazole troches for the prevention of fungal

infections in patients with advanced human immunodeficiency virus in-

fection. N Engl J Med 1995;332:700–5.

138. Meunier F, Paesmans M, Autier P. Value of antifungal prophylaxis with

antifungal drugs against oropharyngeal candidiasis in cancer patients.

Eur J Cancer B Oral Oncol 1994;30B:196–9.

139. Philpott-Howard JN, Wade JJ, Mufti GJ, Brammer KW, Ehninger G, the

Multicentre Study Group. Randomized comparison of oral fluconazole

versus oral polyenes for the prevention of fungal infection in patients at

risk of neutropenia. J Antimicrob Chemother 1993;31:973–84.

140. Phillips P, Zemcov J, Mahmood W, Montaner JS, Craib K, Clarke AM.

Itraconazole cyclodextrin solution for fluconazole-refractory orophar-

yngeal candidiasis in AIDS: correlation of clinical response with in vitro

susceptibility. AIDS 1996;10:1369–76.

141. Dewsnup DH, Stevens DA. Efficacy of oral amphotericin B in AIDS pa-

tients with thrush clinically resistant to fluconazole. J Med Vet Mycol

1994;32:389–93.

142. Bonacini M, Young T, Laine L. The causes of esophageal symptoms in

human immunodeficiency virus infection: a prospective study of 110

patients. Arch Intern Med 1991;151:1567–72.

143. Bhatia V, Kochhar R, Talwar P, Gupta NM, Mehta SK. Association of

Candida with carcinoma of esophagus. Indian J Gastroenterol 1989; 8:

171–2.

144. Wilcox CM, Straub RF, Clark WS. Prospective evaluation of oropharyngeal

findings in human immunodeficiency virus–infected patients with esoph-ageal ulceration. Am J Gastroenterol 1995;90:1938–41.

145. Wilcox CM, Alexander LN, Clark WS, Thompson SE 3rd. Fluconazole

compared with endoscopy for human immunodeficiency virus–infected

patients with esophageal symptoms. Gastroenterology 1996;110:1803–9.

146. Laine L, Dretler RH, Conteas CN, et al. Fluconazole compared with ke-

toconazole for the treatment of Candida esophagitis in AIDS: a ran-

domized trial. Ann Intern Med 1992;117:655–60.

147. Barbaro G, Barbarini G, Calderon W, Grisorio B, Alcini P, Di Lorenzo G.

Fluconazole versus itraconazole for Candida esophagitis in acquired im-

munodeficiency syndrome: Candida esophagitis. Gastroenterology 1996;

111:1169–77.

148. Barbaro G, Barbarini G, Di Lorenzo G. Fluconazole vs. flucytosine in the

treatment of esophageal candidiasis in AIDS patients: a double-blind,

placebo-controlled study. Endoscopy 1995;27:377–83.

149. Barbaro G, Barbarini G, Di Lorenzo G. Fluconazole vs. itraconazole-flucytosine association in the treatment of esophageal candidiasis in

AIDS patients: a double-blind, multicenter, placebo-controlled study.

The Candida Esophagitis Multicenter Italian Study (CEMIS) Group.

Chest 1996;110:1507–14.

150. Wilcox CM, Darouiche RO, Laine L, Moskovitz BL, Mallegol I, Wu J. A

randomized, double-blind comparison of itraconazole oral solution and

fluconazole tablets in the treatment of esophageal candidiasis. J Infect

Dis 1997;176:227–32.

151. Eichel M, Just-Nubling G, Helm EB, Stille W. Itraconazole suspension

in the treatment of HIV-infected patients with fluconazole-resistant or-

opharyngeal candidiasis and esophagitis. Mycoses 1996;39(Suppl 1):

102–6.




152. Lake DE, Kunzweiler J, Beer M, Buell DN, Islam MZ. Fluconazole versus

amphotericin B in the treatment of esophageal candidiasis in cancer

patients. Chemotherapy 1996;42:308–14.

153. Laine L. The natural history of esophageal candidiasis after successful treat-

ment in patients with AIDS. Gastroenterology 1994;107:744–6.

154. Agresti MG, de Bernardis F, Mondello F, et al. Clinical and mycologicalevaluation of fluconazole in the secondary prophylaxis of esophageal

candidiasis in AIDS patients: an open, multicenter study. Eur J Epide-

miol 1994;10:17–22.

155. Fichtenbaum CJ, Powderly WG. Refractory mucosal candidiasis in patients

with human immunodeficiency virus infection. Clin Infect Dis 1998;26:

556–65.

156. Martins MD, Lozano-Chiu M, Rex JH. Declining rates of oropharyngeal

candidiasis and carriage of Candida albicans associated with trends to-

ward reduced rates of carriage of fluconazole-resistant C. albicans in

human immunodeficiency virus–infected patients. Clin Infect Dis 1998;

27:1291–4.

157. Webb BC, Thomas CJ, Willcox MD, Harty DW, Knox KW. Candida-as-

sociated denture stomatitis. Aetiology and management: a review. I. Fac-

tors influencing distribution of Candida species in the oral cavity. Aust

Dent J 1998;43:45–50.

158. Dixon DL, Breeding LC, Faler TA. Microwave disinfection of denture base

materials colonized with Candida albicans. J Prosthet Dent 1999;81:

207–14.

159. Elewski BE. Large-scale epidemiological study of the causal agents of on-

ychomycosis: mycological findings from the multicenter onychomycosis

study of terbinafine. Arch Dermatol 1997;133:1317–8.

160. Korting HC, Schafer-Korting M, Zienicke H, Georgii A, Ollert MW. Treat-

ment of tinea unguium with medium and high doses of ultramicrosize

griseofulvin compared with that with itraconazole. Antimicrob Agents

Chemother 1993;37:2064–8.

161. Ryder NS, Wagner S, Leitner I. In vitro activities of terbinafine against

cutaneous isolates of Candida albicans and other pathogenic yeasts. An-


162. Petranyi G, Meingassner JG, Mieth H. Activity of terbinafine in experi-

mental fungal infections of laboratory animals. Antimicrob Agents

Chemother 1987;31:1558–61.163. Roberts DT. Oral therapeutic agents in fungal nail disease. J Am Acad

Dermatol 1994;31(Suppl 3):S78–81.

164. de Doncker P, van Lint J, Dockx P, Roseeuw D. Pulse therapy with one-

week itraconazole monthly for three or four months in the treatment of

onychomycosis. Cutis 1995;56:180–3.

165. Roseeuw D, De Doncker P. New approaches to the treatment of onycho-

mycosis. J Am Acad Dermatol 1993;29:S45–50.

166. Kirkpatrick CH. Chronic mucocutaneous candidiasis. Eur J Clin Microbiol

Infect Dis 1989;8:448–56.

167. Burke WA. Use of itraconazole in a patient with chronic mucocutaneous

candidiasis. J Am Acad Dermatol 1989;21:1309–10.

168. Smith KJ, Warnock DW, Kennedy CT, et al. Azole resistance in Candida

albicans. J Med Vet Mycol 1986;24:133–44.

169. Horsburgh CR, Kirkpatrick CH. Long-term therapy of chronic mucocu-

taneous candidiasis with ketoconazole: experience with twenty-one pa-tients. Am J Med 1983;74:23–9.

170. Reef SE, Levine WC, McNeil MM, et al. Treatment optionsfor vulvovaginal

candidiasis: background paper for development of 1993 STD treatment

recommendations. Clin Infect Dis 1995;20(Suppl 1):S80–90.

171. Sobel JD, Chaim W. Treatment of Candida glabrata vaginitis:a retrospective

review of boric acid therapy. Clin Infect Dis 1997;24:649–52.

172. Sobel JD, Faro S, Force RW, et al. Vulvovaginal candidiasis: epidemiolog-

ical, diagnostic, and therapeutic considerations. Am J Obstet Gynecol1998;178:203–11.

173. Sobel JD, Vazquex JA. Symptomatic vulvovaginitis due to fluconazole-

resistant Candida albicans in a female who was not infected with human

immunodeficiency virus. Clin Infect Dis 1996;22:726–7.

174. Sobel JD. Recurrent vulvovaginal candidiasis. A prospective study of the

efficacy of maintenance ketoconazole therapy. N Engl J Med 1986;315:

1455–8.

175. Slavin MA, Osborne B, Adams R, et al. Efficacy and safety of fluconazole

prophylaxis for fungal infections after bone marrow transplantation: a

prospective, randomized, double-blind study. J Infect Dis 1995;171:

1545–52.

176. Goodman JL, Winston DJ, Greenfield RA, et al. A controlled trial of flu-

conazole to prevent fungal infections in patients undergoing bone mar-

row transplantation. N Engl J Med 1992;326:845–51.

177. Bow E, Laverdiere M, Lussier N, Rotstein C, Ioannou S. Anti-fungal pro-

phylaxis in neutropenic cancer patients [abstract LM-88]. In: Program

and abstracts of the 37th Interscience Conference on Antimicrobial

Agents and Chemotherapy (Toronto, Canada). Washington, DC: Amer-

ican Society of Microbiology, 1997.

178. Walsh TJ, Hiemenz J, Pizzo PA. Evolving risk factors for invasive fungal

infections: all neutropenic patients are not the same [editorial response].


179. Karchmer AW, Samore MH, Hadley S, Collins LA, Jenkins RL, Lewis WD.

Fungal infections complicating orthotopic liver transplantation. Trans

Am Clin Climatol Assoc 1994;106:38–48.

180. Hadley S, Samore MH, Lewis WD, Jenkins RL, Karchmer AW, Hammer

SM. Major infectious complications after orthotopic liver transplanta-

tion and comparison of outcomes in patients receiving cyclosporine or

FK506 as primary immunosuppression. Transplantation 1995;59:851–9.

181. Collins LA, Samore MH, Roberts MS, et al. Risk factors for invasive fungal

infections complicating orthotopic liver transplantation. J Infect Dis1994;170:644–52.

182. Kung N, Fisher N, Gunson B, Hastings M, Mutimer D. Fluconazole

prophylaxis for high-risk liver transplant recipients. Lancet 1995;349:

1234–5.

183. Tollemar J, Hockerstedt K, Ericzon BG, Jalanko H, Ringden O. Liposomal

amphotericin B prevents invasive fungal infections in liver transplant

recipients: a randomized, placebo-controlled study. Transplantation

1995;

59:45–50.

184. Linden P, Kramer DJ, Mazariegos G, et al. Low-dose amphotericin B for

the prophylaxis of serious Candida infections in high-risk liver recipients

[abstract J47]. In: Program and abstracts of the 36th Interscience Con-

ference on Antimicrobial Agents and Chemotherapy (New Orleans).

Washington, DC: American Society for Microbiology, 1996.

185. Benedetti E, Gruessner AC, Troppmann C, et al. Intra-abdominal fungalinfections after pancreatictransplantation:incidence,treatment,and out-

come. J Am Coll Surg 1996;183:307–16.

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